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Cite this: Chem. Soc. Rev., 2011, 40, 27192740

www.rsc.org/csr CRITICAL REVIEW

Chemistry in human telomere biology: structure, function and targeting
of telomere DNA/RNA
Yan Xu*
Published on 07 February 2011 on http://pubs.rsc.org | doi:10.1039/C0CS00134A

Received 5th October 2010

DOI: 10.1039/c0cs00134a

Telomeres are present at the ends of all eukaryotic chromosomes. Human telomeres play an important
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role in critical processes underlying genome stability, cancer, and aging, and their importance was
recognized via the award of the 2009 Nobel Prize in Physiology or Medicine. Chemistry has made vast
and almost unparalleled contributions to telomere biology. This critical review highlights the
contributions of chemistry in human telomeres and summarizes the signicant development of human
telomere biology. First, I provide an overview of the advances in understanding of the structures and
functions of human telomeres. Second, I focus on the current eorts on developing various chemical
approaches to targeting human telomeres and telomerase for the treatment of cancer. Third, studies on
a newly discovered telomeric repeat-containing RNA are discussed in detail. Last, future challenges in
the eld are outlined, including perspectives of both chemistry and biology (412 references).

1. Introduction telomeres protect chromosomes from end-to-end fusion.13

The telomere history was beginning to nd the special properties
of chromosome ends (Fig. 1). Landmark observations by
Muller and McClintock in the 1930s and 1940s indicated that
Division of Chemistry, Department of Medical Sciences, Faculty of
Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki,
889-1692, Japan. E-mail: xuyan@mkomi.rcast.u-tokyo.ac.jp,
xuyan@fc.miyazaki-u.ac.jp; Fax: +81 0985-85-0993;
Tel: +81 0985-85-0993
Yan Xu earned his PhD at
Tokyo Medical and Dental
University, where he studied
non-natural nucleic acids and
small molecules to stabilize
Z-form DNA and photo-
chemical methods of probing
telomere G-quadruplex struc-
tures. Then he won a Japan
Science and Technology Fellow-
ship at Kyoto University,
studying the structure and
function of DNA by chemical
approaches. He became an
Yan Xu assistant professor at The
University of Tokyo in 2007.
Currently, he is an associate professor at the Faculty of
Medicine, University of Miyazaki. His group focuses on (i)
understanding structure and function of human telomere DNA
and RNA, (ii) developing chemical approaches to targeting
human telomere for discovering anticancer agents.
The word telomere is derived from the Greek nouns telos
meaning end and meros meaning part. Though crucial for
many cellular functions, telomeres are subject to progressive
decreases in length. Small DNA segments at each telomere cannot
be copied and are lost during DNA replication and cell division.
This puzzle was referred as the end replication problem.4
Reaching the critical point of telomere shortening (the Hayick
limit)57 leads cells to senescence or death, and it is assumed that
this may serve as a molecular clock for cellular lifespan. The
existence of a reverse transcriptase that could synthesize telomeric
DNA, discovered in 1985 by Greider and Blackburn, named after
telomerase, provided the experimental answer to this problem.8 A
few years later, homologous recombination between telomeric
sequences was also shown to elongate telomeres by the alter-
native lengthening of telomeres pathway (ALT).9
There are still other fundamental problems with the ends of
linear chromosomes. Natural chromosome ends are recognized
as double-stranded breaks and get degraded by nucleases.1015
Telomeres provide critical protection of chromosomes from
such detriments. It has been suggested that the protective
function of telomeres might depend on their state, e.g.,
whether they have capping or uncapping structures.1623
Telomeres have been likened to the aglets (tips) on the ends of
shoelaces that keep them from fraying. Recent studies suggest
that telomeres may form higher order structures to achieve the
capping function.2325 The contributions of both telomere
DNA and various telomere-binding proteins to such structures
have gained appreciation.2628 What are the structural features
of telomeres and through which mechanisms do they ensure
chromosome end protection? What is the molecular basis of
the telomeric cap?

This journal is c The Royal Society of Chemistry 2011 Chem. Soc. Rev., 2011, 40, 27192740 2719
 View Online

Fig. 1 Timeline of telomere studies.

Telomerase or its telomere DNA substrate was rst

Published on 07 February 2011 on http://pubs.rsc.org | doi:10.1039/C0CS00134A

recognized as a unique and exciting anticancer target and has

been a major focus in cancer research since the mid-1990s.2946
The key advantages of targeting telomerase or telomeres
in comparison with most other cancer targets are their
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relative universality, criticality, and specicity for cancer

cells.4760 Recently, telomere function has been directly
implicated in several other diseases such as dyskeratosis
congenita and idiopathic pulmonary brosis.6170 Chemical
approaches have been developed for targeting human telomeres
and telomerase for cancer therapy.7174 What is a structural
basis for the inhibition mechanism? What are the prospects for
the use of anti-telomerase and anti-telomere agents as drugs?
For a long time, telomeres have been considered to be
transcriptionally silent. A recent nding demonstrated that
telomere DNA is transcribed into telomeric repeat-containing
RNA (TERRA).75,76 Telomeric RNA, a newly emerging
player in telomere biology, may be a key component of
telomere machinery.77 Studies of telomeres have focused on
telomere DNA and its related proteins. The identication of
TERRA RNA in the chromosome end may change this Fig. 2 The green staining marks the telomeres.
situation. What are the structures and functions of human
telomeric RNA? How is telomeric RNA specically associated For example, duplex DNA can adopt a variety of sequence-
with telomeric DNA? dependent secondary structures that range from the canonical
The understanding of telomeres and telomerase is expected right-handed B form to the left-handed Z form.90,91 Triplex
to provide major insights into genome stability, cancer, and and tetraplex DNA structures are also known to exist.9193
telomere-related diseases. Fundamental knowledge from many Such local DNA conformations have been suggested to be
elds, including chemistry, structural biology, cell biology, biologically important in processes such as DNA replication,
and medicinal chemistry, have opened up the possibility of gene expression and regulation, and DNA damage repair.92,93
targeting telomerase, telomeres, and telomere-binding proteins For example, Z-DNA, a left-handed DNA conformation that
in therapeutic strategies against cancer and aging-related favors alternating GC sequences, is required for chromatin-
pathologies. Thousands of publications and numerous review dependent activation of the colony stimulating factor-1
articles have described signicant advances and key questions (CSF1) promoter.94
of human telomeres.7888 This review will highlight the Human telomeric DNA consists of a duplex region
contribution of chemistry to human telomeres, especially in composed of TTAGGG repeats, which terminates in a
the detailed chemical structure of telomere DNA at the atomic 100200-nucleotide (nt) G-rich single-stranded overhang.9597
level and the status of chemistry-based challenges of drug Fluorescent in situ hybridization showing human telomeres is
development. The intention of this article is not to shown in Fig. 2, indicating that telomeres are present at the
exhaustively cover the sphere of human telomere research, ends of chromosomes. Two structures of the 3 0 single-stranded
but to provide both insight and inspiration in the eld and overhang have been proposed: one suggests the formation of
stimulate further research to develop new chemical G-quadruplexes, while the other proposes the presence of a
approaches. t-loop.

2. Human telomere structure
Besides encoding genetic information, DNA itself can take on
conformations other than the right-handed B-DNA structure.8991
2.1 G-quadruplex
G-quadruplexes are formed by the stacking of several
G-tetrads and are constituted by four backbone strands
in which several loops connect these strands (Fig. 3).

2720 Chem. Soc. Rev., 2011, 40, 27192740 This journal is c The Royal Society of Chemistry 2011

Fig. 3 Four guanines are arranged in a plane to form the G-tetrad by
Published on 07 February 2011 on http://pubs.rsc.org | doi:10.1039/C0CS00134A
hydrogen bonds. G-quadruplexes are formed by the stacking of several
G-tetrads.
Four guanines are arranged in a plane to form the G-tetrad by
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hydrogen bonds and are stabilized by cations. The assembly of
guanine and its analog was discovered to form gels in 1910,
and diraction studies by Gellert et al. in 1962 revealed the
tetrameric arrangement between guanosine residues.98 A wider
interest in such structures has promoted two international
meetings on this exciting topic.99101
A large number of dierent structures have been observed in
the human telomere.102111 The dierent G-quadruplex topologies
may be associated with some related aspects: the syn/anti
conformation of guanine residues, the relative orientation of
the G-quartet core, the types of linking loops, the sequences
and lengths of telomere DNA, and the nature of the associated
metal cations.112118
Early NMR studies suggested that human telomeric
sequences d(TTAGGG) and d(TTAGGGT) form a parallel
G-quadruplex in K+ solution with three G-tetrads in all anti-
guanines and lack of linking loops (Fig. 4a).119 Dimerization
of two such G-quadruplexes was demonstrated to occur
through end-to-end stacking of 3 0 -terminal G-tetrads
(Fig. 4b).119,120 For the d(AGGGT) and d(TTAGGGT), a
novel A-tetrad was formed to stabilize the G-quadruplex, in
which four adenines were held together in a plane by hydrogen
bonds.121,122
The K+-stabilized crystal structure of d(AGGGTTAGGGT)
has been determined as shown in Fig. 4c,123 indicating a
parallel G-quadruplex with two external loops abutting the
sides of the G-tetrads and guanines in anti conformation. A
TATA tetrad was observed in the dimer structure. In K+ only two G-tetrads together with a ve-nucleotide diagonal
solution, the same sequence adopts two dimeric parallel and
antiparallel G-quadruplexes, as reported by NMR studies.124
The parallel form is similar to the K+-stabilized crystal
structure observed in the crystalline state (Fig. 4c). The anti-
parallel form has the opposing GGG columns with lateral
loops on the ends of G-quadruplex and the syn/anti mixed
guanines (Fig. 4d). Similarly, a human telomeric sequence
d(GGGTTAGGG) was shown to form both antiparallel and
parallel bimolecular tetraplexes in K+-containing solutions.125,126
In Na+ solution, the two similar sequences were suggested to
adopt the antiparallel-stranded G-quadruplexes.126,127 For
d(TTAGGGTTAGGG), Na+ induces a tetrameric antiparallel
G-quadruplex (Fig. 4d), whereas K+ stabilizes the dimeric
parallel and tetrameric antiparallel structures.128 The tetrameric
structure is made up of four strands with antiparallel orientation
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(Fig. 4e), in which the interveningTTAbases that
occur between G-tetrad-forming guanines might form two
WatsonCrick base pairs linking two strands of opposite
polarity.
NMR spectroscopy by Phan et al. dened a dimeric
G-quadruplex formed by 16-mer d(GGGTTAGGGTTAGGGT)
and 6-mer d(TAGGGT) human telomeric sequences (Fig. 4f),
suggesting an association between the two telomere
sequences.129 This structure contains the (3+1) hybrid
G-quadruplex topology, in which three strands are oriented
in one direction and one is oriented in the opposite direction.
In 1993, an antiparallel G-quadruplex of telomeric sequence
d[AGGG(TTAGGG)3] was observed by NMR in Na+ solution
(Fig. 4g).130 NMR analysis by Patel et al. revealed an intra-
molecular basket-type structure in which the opposing GGG
columns are antiparallel, with one diagonal and two lateral
TTA loops and the syn/anti mixed guanines. On the other
hand, the same 22-mer sequence adopts a completely dierent,
propeller-type structure in a crystal grown in the presence of
K+ ions (Fig. 4h).123 In this structure, four core GGGs are
parallel, with the three linking external loops positioned on the
G-quartet core exterior. Tan et al. suggested that the
molecular crowding condition was to stabilize the parallel
G-quadruplex conformation.131,132
In physiologically-relevant K+ solution, various four-
repeat sequences show several very distinct folds. The
d[AGGG(TTAGGG)3], d[TAGGG(TTAGGG)3], and
d[TTAGGG(TTAGGG)3] sequences adopt a hybrid-type
G-quadruplex in which the loop types from the 5 0 end to the
30 end are external, lateral, and lateral (Fig. 4i),133139 whereas the
d[TAGGG(TTAGGG)3TT] and d[TTAGGG(TTAGGG)3TT]
sequences form the hybrid-type G-quadruplex that diers in
the order of loop arrangements,137,139,140 i.e., lateral, lateral,
and external from the 5 0 end (Fig. 4j). The sequence
d[TAGGG(TTAGGG)3T] can interconvert the two orders of
loop arrangements in K+ solution.111,139 In addition, the
d[AGGG(TTAGGG)3] sequence can fold into another anti-
parallel conformation, the so-called chair with the lateral
loops at the bottom of the G-quadruplex (Fig. 4k).133,141
Recently, an anti-parallel basket-type G-quadruplex formed
by the d[GGG(TTAGGG)3T] sequence in K+-containing
solutions has been identied by NMR studies (Fig. 4l) that
is very dierent from the other known topologies, involving
loop and two lateral loops.142 The d[GGG(TTAG3)4] sequence
in K+ solutions was suggested for example to form a hybrid-
type G-quadruplex in which the extra TTAGG repeat was
used to generate an external loop (Fig. 4m).126 The conformational
diversity of human telomeric G-quadruplexes in K+ solution
conrms that a particular topology is not only associated with
some related external aspects but is also dependent on its own
sequence, the 5 0 and 3 0 end sequences in particular. Other
G-quadruplex folds have been proposed for human telomeric
sequences under dierent experimental conditions.125,126,143146
Short human telomeric sequences as models for structural
studies of the telomere have provided important information
for understanding the structure of human telomeres. Little is
known, however, about the structure of longer overhang
sequences of the telomere repeat. Most studies have focused
Chem. Soc. Rev., 2011, 40, 27192740 2721

Published on 07 February 2011 on http://pubs.rsc.org | doi:10.1039/C0CS00134A
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Fig. 4 Schematic structures of human telomeric G-quadruplexes and i-motif. AFM image of higher-order telomeric DNA structures.
on individual G-quadruplexes formed by short telomeric
DNA (especially 22-mer unimolecular G-quadruplexes).
However, it might be more biologically relevant to take into
account the real length of the 3 0 -terminal single-stranded
overhang of human telomeric DNA in vivo (100200 nt) to
directly reveal the structural features of long-telomeric-overhang
DNA, owing to its similarity in length to that of the intra-
cellular telomere.
In 2002, Parkinson and Neidle et al. suggested that oligo-
merization of individual parallel G-quadruplexes can be simply
performed to form a higher-order structure by inserting an
additional TTA loop to each 22-mer structure (Fig. 4n).123 A
series of computational methods has been used to characterize
the properties of the higher-order G-quadruplex with parallel-
stranded topology, conrming that the overall multimer
G-quadruplex becomes more stable with the addition of
further G-tetrads and that the TTA loop is the most exible
part of the model.147 The unique topology of the hybrid-type
2722 Chem. Soc. Rev., 2011, 40, 27192740
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structure was suggested to facilitate stacking of the 22-mer
telomere units into higher-order packing structures (Fig. 4o).
Because the 5 0 and 3 0 ends of the hybrid-type G-quadruplex
point in opposite directions, this structure should easily fold
into a higher-order packing structure by consecutive formation
of G-quadruplex units. End-to-end connection is simply
accomplished by a TTA linker to connect each 22-mer
G-quadruplex structure. To gain structural information on
human single-stranded telomeric-overhang DNA, we visualized
the elongated telomere sequence by atomic force microscopy
(AFM).148 The AFM image clearly shows that the higher-
order G-quadruplex consists of blob-shaped protrusions
arranged end-to-end and formed by adjacent G-quadruplex
units (Fig. 4p).133,134 In further support of the dimeric
G-quadruplex, a study by molecular dynamics simulation
showed a stable dimeric G-quadruplex structure for human
telomeric DNA in which the interface between G-quadruplex
units is stabilized by specic stacking interactions of loop
This journal is c The Royal Society of Chemistry 2011

nucleotides (Fig. 4q).149 In other models, the G-quadruplexes
formed by long telomeric DNAs are beads-on-a-string gave some structural information, the concentration of
structures (Fig. 4r).150 In this structure, two G-quadruplex
units are connected by one linker without a stacking inter-
action between the units and they can move relatively
independently of each other.
2.2 G-quadruplex probe
To gain a better understanding of telomere DNA conformations,
various studies have been performed using platinum cross-
linking, FRET,125I-radioprobing, covalent ligation, click
reaction, sedimentation, and small molecule probes.151159
Published on 07 February 2011 on http://pubs.rsc.org | doi:10.1039/C0CS00134A
We developed a photochemical method to distinguish between
parallel and anti-parallel telomere G-quadruplexes.160 The
photoreactivity of iodouracil-containing human telomeric
DNA is highly dependent on the DNA structure. A photo-
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reaction product, the 20 -deoxyribonolactone residue, is eectively
produced only in the diagonal loop of the anti-parallel
G-quadruplex (Fig. 5a). As 5-halouracil-substituted DNA is
functional in living cell systems such as Escherichia coli, use of
the photochemical reaction of 5-halouracil-containing DNA
would provide a powerful tool to probe telomere G-quadruplex
conformations in living cells.
In a study using platinum cross-linking, only antiparallel
G-quadruplex conformation was detected in both Na+- and
K+-containing solutions.151 Single-molecule uorescence
energy transfer revealed that the antiparallel and parallel
structures can coexist and interconvert under near-physiological
conditions.152,153 The conformational diversity of human telomeric
G-quadruplexes is demonstrated by using 125I-radioprobing
based on the comparison of the probability of breaks with
the distance from 125I to the corresponding nucleotides.141
Chemical ligation occurring at loop positions of unimolecular
G-quadruplexes is also used to explore the various solution
conformations of human telomere sequences.154 More recently,
a study utilizing double-nitroxide-modied (spin label) telomeric
sequences demonstrates the presence of a 1 : 1 mixture of the
parallel and antiparallel G-quadruplex structures in solution
by investigating the distance between the spin-labeled nucleo-
tides in the dierent G-quadruplexes (Fig. 5b).161
Using a single-chain antibody, Schatzel et al. suggested
that Stylonychia lemnae telomeric DNA forms an anti-parallel
G-quadruplex in vivo, in which about 2  108 telomeres are
Fig. 5 (a) A photochemical method was used to distinguish between
parallel and anti-parallel telomere G-quadruplexes. (b) The distance
between the spin-labeled nucleotides (orange arrows) in the dierent
G-quadruplexes was used to determine these conformations.
This journal is c The Royal Society of Chemistry 2011
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present in one macronucleus.162 Although these approaches
G-quadruplexes in humans is too low to be detected in the
presence of only a few dozen chromosome ends (92 telomeres
per cell in G1 of the cell cycle and twice as many in G2).
Nucleic acid structures are dicult to probe in vivo; in fact,
direct evidence for human telomeric DNA G-quadruplexes
existing in cells has not yet been obtained. Therefore, a more
eective chemical method of probing G-quadruplex structures
in living cells is desired.163
2.3 T-loop
Using the puried telomeric fragments of human and mouse,
t-loops were rst observed by electron microscopy in 1999.164
Telomeres have been shown to form a t-loop, a lasso-like
structure in which the 3 0 -overhang invades the double-
stranded region of telomeric DNA (Fig. 6a). Although the
atomic-level structural details of the loop are not known, the
G-rich 3 0 overhang must be incorporated into the double-
stranded telomeric region in a manner of base pairing with the
C-strand. The strand invasion takes place at a distance from
the terminal part of the duplex telomere region and, therefore,
results in a large duplex lariat structure. The circular parts of
the t-loops range in size from very small (1 kb) to 425 kb.
A displacement (D) loop is involved in the t-loop in which the
3 0 overhang provides the primer for DNA synthesis and
telomere extension (Fig. 6a). In addition to providing a
mechanism for extension, the D-loop is a dynamic structure,
which can be stabilized by branch migration to form a
Holliday junction (HJ). In order to observe t-loops, it is
necessary to introduce interstrand cross-links with psoralen
and UV. Without the chemical cross-linking treatment that
stabilizes the strand invasion, loops were observed at very low
frequency ratios (o5%).165,166
Fig. 6 (a) t-loop. (b) A lariat model containing G-quadruplex.
(c) A segment containing 16-mer G-tracts can bind to the G-tract of
another segment of telomere DNA by forming G-quadruplex when the
3 0 -end invades the adjacent double-stranded segment of the telomere
to form the t-loop.
Chem. Soc. Rev., 2011, 40, 27192740 2723

Thanks to the cross-linking reaction provided by chemistry,
the t-loop has been obtained as a possible telomere structure
by biologists. However, lack of evidence of their existence in
cells as truly biologically relevant structures remains a
challenging problem. Resolution of this question may have
to await the development of a chemical approach for t-loop
visualization.
2.4 Relationship between G-quadruplex and t-loop
Recently, a structural study suggested that the G-quadruplex
structure can stabilize a relatively large lariat structure
(t-loop).167 The model revealed a possible relationship between
Published on 07 February 2011 on http://pubs.rsc.org | doi:10.1039/C0CS00134A
these two structures in which G-quadruplex formation induces
the 3 0 -overhang strand encroaching into the double-stranded
region (Fig. 6b and c). This model may provide conformational
exibility for chromosome ends in response to environmental
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conditions such as protein binding. Furthermore, another
puzzle raised by the t-loop structure may be solved, as the
fact that it is stabilized by the 3 0 -overhang strand encroaching
into the double-stranded region cannot explain the inhibition
of telomerase activity by a G-quadruplex stabilizing molecule,
as discussed in detail below. The present model indicates that
not only strand encroachment but also G-quadruplex
formation could stabilize the t-loop structure,71,167 which
strikes a happy medium between the G-quadruplex and the
t-loop (Fig. 6c). This may provide the exibility for responding
to environmental conditions as protein binding.
The G-quadruplex confers an energetically preferable
conformation. However, these two structures of the 3 0 end
overhang might also co-exist. Nonetheless, the existence of a
folding of the G-strand overhang into a G-quadruplex has to
be considered most plausible in human cells based on the
available experimental evidence.
2.5 i-motif
It is known that the telomeric C-strand can also fold in a novel
structure, the i-motif, in which two parallel-stranded duplexes
associate in a head-to-tail orientation with intercalation
of the CC+ base pairs (Fig. 4s).168 This structure is stabilized
with a low pH through protonation of cytosines. It has
been indicated that this conformation could participate in
the dynamics of the telomeric DNA duplex and favor its
opening.
3. Telomere-binding proteins
The TTAGGG repeats of human telomeres associate with
the six-protein complex shelterin (Fig. 7). Three shelterin
proteins, TRF1, TRF2, and POT1, directly recognize
telomere DNA sequences, and are interconnected by three
additional shelterin proteins, TIN2, TPP1, and Rap1. Each is
described below.
Telomeric repeat-binding factors 1 and 2 (TRF1 and TRF2)
directly bind the TTAGGG sequences in double-stranded
telomeric DNA by a C-terminal DNA-binding domain.169176
TRF1 has acidic amino acids at its N-terminus, while
TRF2 contains a Gly/Arg-rich domain as the basic domain.
They bind DNA as homodimers or oligomers by homotypic
interactions in the TRF homology (TRFH) domain.
2724 Chem. Soc. Rev., 2011, 40, 27192740
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Fig. 7 Human telomeres associate with the six-protein complex
shelterin.
Protection of telomeres 1 (POT1) directly binds the 3 0 -single-
stranded overhang of the chromosome end in its
N-terminus.177,178 The single-stranded DNA-binding domain
in the N-terminus allows the proteins to bind to arrays of the
sequence TAGGGTTAG with great sequence specicity. It is
suggested that POT1 is able to disrupt the highly folded
intramolecular G-quadruplex structures.179
TRF2- and TRF1-interacting nuclear protein 2 (TIN2)
bridges TRF1 and TRF2 to the TPP1POT1 heterodimer,
therefore linking the duplex component of the telomeres to the
single-stranded overhang.180184 TIN2 interacts with TRF1 at
its C-terminus and associates with a hinge domain of TRF2 at
the N-terminus. Using a third protein interaction site located
in its N-terminus, TIN2 binds to TPP1 and forms a complex.
Therefore, TIN2 binds to TRF1, TRF2, and TPP1 and
occupies a central position in shelterin.
Repressor/Activator protein 1 (Rap1) lacks DNA-
binding activity in human and is dependent on its interaction
with TRF2 for telomere binding.185,186 Rap1 forms a complex
with TRF2 by a C-terminal domain that mediates the
interaction with a short helical region in the hinge domain
of TRF2.
TIN2 and POT1 interacting protein 1 (TPP1) interacts with
POT1 and TIN2 by the POT1-binding domain and C-terminal
of TIN2.187 The connection with TPP1 is critical for the
association of POT1 with telomeres, providing a main way
by which POT1 is recruited to telomeres.188,189
Several telomeric DNA-binding proteins have been found
to associate with telomere G-quadruplex. POT1 is known
to disrupt the telomeric G-quadruplex, allowing for
telomerase extension.179 Conversely, yeast Rap1 is believed
to bind telomeric DNA to promote G-quadruplex
formation,190 whereas human RaP1 is recruited to
telomeres by TRF2. TRF2 has also been shown to bind and
promote the t-loops. Taken together, the shelterin
complex, despite consisting of only six proteins, has an
immensely complex role in telomere regulation and protection
and in the control of signaling cascades from the
chromosome ends.
In a recent study, biochemical purication of the telomeric
complexes showed that approximately 200 telomere-
associated proteins that interacted with and might inuence
telomeric structure may exist in human cells.191 The great
diversity of telomere components provides a hint about the
presence of highly plastic organization of human telomeres.
This journal is c The Royal Society of Chemistry 2011

4. Functions of telomeres
Terminals of linear DNA are recognized as DNA strand
breaks, leading to activation of DNA damage signals. Similarly,
the disruption of telomere maintenance results in chromosome
end-to-end fusions and/or ends being recognized as DNA
damage. The DNA damage machinery activates two independent
signaling pathways in cells: (i) the ATM (ataxia telangiectasia
mutated) kinase pathway and (ii) the ATR (ataxia telangiectasia
and Rad3-related) kinase pathway. In addition, double-
stranded break repair via the non-homologous end joining
(NHEJ) or homologous recombination (HR) DNA repair
pathways results in inappropriate chromosomal end-to-end
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fusions. It was suggested that cells respond to dysfunctional
telomeres by undergoing senescence, apoptosis, or genomic
instability. Telomeres must perform the crucial job of
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protecting the chromosomes from DNA damage responses,
degradation, and fusion. This protection must include
mechanisms that block the two kinase pathways at the
telomeres and allow the telomeres to avoid both repair
reactions. It is not clear how the 3 0 end overhang provides
protection from the abnormal pathways, but the most widely
accepted hypothesis is that the capping state in the chromo-
some ends serves to protect the telomere ends (Fig. 8).
The t-loop and G-quadruplex provide the possible cap
states for telomere protection. Telomere loss leads to eventual
telomere uncapping, that is, disruption of the proper structure
of the protective cap at the end of the telomere.1625 Telomere
loss leads to the disruption of the proper telomere structures,
that is, induction of eventual telomere uncapping at the end of
the telomere.1625 With the perturbed structures, the linear
chromosome ends are identied by the cells DNA damage
surveillance machinery as DNA breaks, which can lead to
many types of genome aberrations.192
Although the t-loop provides a possible structure for
telomere protection, many questions still remain to be
answered. Binding of replication protein A (RPA) to the
single-stranded region in the t-loop could lead to the
activation of ATR kinase at the telomere.21 Consistently, a
recent study showed that the 3 0 end overhang length, seemingly
sucient for t-loop formation, does not provide a protective
structure for prevention of senescence in cells.193 Our recent
studies reveal that a higher-order DNA G-quadruplex
structure protects DNA double-stranded ends from being
recognized as double-stranded breaks and directs against
Fig. 8 Telomeres are a lot like aglets on the ends of shoelaces that
keep them from fraying. A capping structure in the chromosome
ends serves to protect the telomere ends. An uncapping structure
results in the telomere dysfunction, which is likened to the loss of
aglets inducing the fraying.
This journal is c The Royal Society of Chemistry 2011
View Online
nuclease hydrolysis, suggesting that this superhelix structure
might be important for eectively packing telomeric DNA
into a protective capping state.
The t-loop and G-quadruplex provide the cap states for the
telomere. However, these structures need to be exible, as the
t-loop during DNA replication and the telomeres may adopt a
more open state, allowing them to be extended by telomerase.
5. Telomere-related diseases
Several human diseases are associated with telomere
shortening, such as heart disease, ulcerative colitis, liver
cirrhosis, and atherosclerosis, and several premature aging
syndromes.194197 A rst discovered disease, dyskeratosis
congenita, has shorter telomeres and unstable telomerase
because of mutations in components of the telomerase
complex.198200 Aplastic anemia has been reported to be
associated with mutations in the genes encoding aplastic
anemia or telomere-binding protein.201,202 Recently, accelerated
telomere shortening has also been found in some cases of
idiopathic pulmonary brosis.203 In addition, mouse models of
telomerase deciency as well as telomeres shortening in human
disease have suggested that aging pathologies are associated
with Werner and Bloom syndrome and ATM syndrome,
further demonstrating that short telomeres contribute to the
pathobiology of these premature ageing diseases.204206
Telomere shortening and telomerase deciency associated
with these human diseases suggest that strategies of telomerase
reactivation and telomere elongation might have therapeutic
potential for such premature aging syndromes.207 In a
previous study, it has been demonstrated that expression of
the catalytic subunit of human telomerase (hTERT) induces
telomerase activity and telomere elongation, resulting in a
greatly extended lifespan for a variety of human cell types.208
Therapeutic agents that could be designed to stimulate the
alternative lengthening of the telomere pathway (ALT) would
preferentially maintain telomere length. Several reports have
suggested that small molecules can extend the lifespan of
lymphocytes by activating telomerase, and such molecules
might potentially lead to treatments for these patients
(Fig. 9).207,209
6. Anticancer agents: chemical approaches to
target human telomeres and telomerase
Human telomerase is a cellular reverse transcriptase.8,210 It is
composed of two essential components: functional telomerase
RNA (hTR) which serve as templates for the addition of
telomeric repeats and the telomerase reverse transcriptase
catalytic subunit (hTERT).
Fig. 9 Chemistry approaches provide molecule activators.
Chem. Soc. Rev., 2011, 40, 27192740 2725
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Telomerase was rst recognized as a unique and exciting telomere duplex DNA has been developed by conjugation of
anticancer target about 5 years after its discovery. Telomerase PyrroleImidazole polyamides and alkylating moieties.236
is activated in 8090% of human tumors of all cancer types,30
including cancer stem cells.211 No other tumor-associated gene 6.2 Nucleoside analogues
is as widely expressed as telomerase in cancers. This generality
Several nucleoside analogs are also reported to be promising
makes telomerase an important drug target for cancer.2960,212
agents with cell type specicity.237 These chemically synthesized
The fact that telomerase is low or undetectable in most normal
nucleosides act as chain-terminating inhibitors of reverse
cells provides tumor specicity to telomerase-based anticancer
transcriptases when they are incorporated into the DNA by
drugs, as this may reduce the undesired side eect of damaging
telomerase.238,239 Examples include azidothymidine (AZT)
normal cells. Thus, telomerase or its telomere DNA substrate
(Fig. 11b),240,241 6-thio-2 0 -deoxyguanosine 5 0 -triphosphate
presents a target with good selectivity for tumors over healthy
(TDG-TP),242 and L-enantiomers (L-dTTP and L-dGTP).243
tissue. Numerous approaches have been developed, including
20 ,30 -Dideoxyguanosine 50 -triphosphate, carbovir 50 -triphosphate,
Published on 07 February 2011 on http://pubs.rsc.org | doi:10.1039/C0CS00134A

the targeting of the two major components hTERT and

and D-carbocyclic-2 0 -deoxyguanosine 5 0 -triphosphate have also
hTR of telomerase, and the telomeres themselves (Fig. 10).
an inhibitory eect on telomerase.244
There are several late-stage trials in the pipeline.
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6.3 Oligonucleotide derivatives

6.1 Small molecule compounds
It has been suggested that some chemical approaches have
A variety of small molecule compounds, including screened been directed to the 451-mer long human telomerase RNA
chemical libraries of reverse transcriptase inhibitors, have been (hTR), with special focus on the 11-mer template region
shown to directly interact with the hTERT component of (5 0 -CUAACCCUAAC-3 0 ). Antisense, ribozyme, or small
telomerase. One having a potent compound with good interfering RNA (siRNA) agents targeting hTR exhibit telomerase
activity, BIBR1532, led to telomerase inhibition and telomere inhibitory activity.244,245 One such oligonucleotide (GRN163L)
shortening (Fig. 11a).213215 Other catalytic inhibitors, epicatechin prevents hTR from forming an active complex with hTERT
(EGCG and MST312),216,217 isothiazolone (TMPI),218 and and has recently been entered into Phase I/II clinical
bisindole derivatives,219 are highly selective for telomerase. trials.246258 This 13-mer oligonucleotide is chemically
Nitrostyrene,220 quinoxaline,221 and rubromycin analogues222 modied through the use of a phosphorothioate (PS) linkage
have been shown to inhibit the activity of the telomerase
enzyme. A number of compounds, such as helenalin and
chrolactomycin,223,224 also showed activity against telomerase.
Other types of molecules, such as histone deacetylase (HDAC)
inhibitors,225,226 COX-2 inhibitors,227 and tyrosine kinase
inhibitors,228 have an inhibitory eect on telomeres and telomerase
as well as on a number of cellular processes.229,230 These
compounds also include telomerase-specic phosphorylation
inhibitors (bis-indolylmaleimide I and H-7),231 nonsteroidal anti-
inammatory drugs such as aspirin,232 and antioxidants such as
vitamin E.233 Thapsigargin inhibits telomerase by increasing
intracellular calcium concentrations.234
Several small compounds binding to the RNA/DNA
heteroduplex were identied to inhibit the enzyme by either Fig. 11 (a) Small molecule BIBR1532 interacts with the hTERT.
preventing strand dissociation or suciently distorting the (b) Nucleoside analogue AZT. (c) Oligonucleotide derivative
substrate.235 Recently, an approach for alkylating human GRN163L. (d) Telomerase siRNA.

Fig. 10 Telomerase or its telomere DNA substrate presents a target for cancer. Numerous approaches have been developed, including the
targeting of the two major components hTERT and hTR of telomerase, and the telomeres themselves.

2726 Chem. Soc. Rev., 2011, 40, 27192740 This journal is c The Royal Society of Chemistry 2011
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to prevent enzymatic degradation and by linking a lipid 6.5 Structure-based agents

palmitate moiety to its end to enhance cellular uptake
Folding of telomeric DNA into G-quadruplexes inhibits
(Fig. 11c).
telomerase by locking the single-stranded telomeric substrate
Chemical modication on nucleic acid-based drugs has
into an inactive conformation that is no longer recognized, nor
provided several agents with potential anticancer activity.
elongated, by the enzyme.290 Telomerase has been shown to
These modied molecules bind RNA sequences with improved
function in telomere protection as well as in telomere
selectivity, enhanced ecacy, and improved pharmacological
elongation.291,292 The inability of telomerase to access the
properties.
telomere is able to activate telomere length-independent
2 0 -O-methyl (2 0 -O-Me) and 2 0 -O-(2-methoxyethyl) (20 -MOE)
damage signal causing immediate cell arrest or death.
modied RNAs can eciently and sequence-selectively inhibit
G-quadruplex formation also blocks the single-stranded binding
telomerase, causing telomeres to shorten and cell proliferation
protein hPOT1 to telomere,293,294 leading to a disruption
to decrease.259,260 2 0 ,5 0 -Oligoadenylate oligonucleotides
between telomere and shelterin complex. Recently, it was also
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directed against the template region of hTR also eciently

suggested that G-quadruplexes can cause the deletion of
inhibit telomerase.261,262 An oligonucleotide, 20 ,5 0 -oligoadenylate
telomere lagging strand, resulting in a dominant factor in
(2-5A-anti-hTR), inhibits human telomerase by specically
the telomere shortening.295,296 Complete replication of
and eectively degrading the targeted RNA.263265 Combining
telomeric ends requires unwinding higher-order structures of
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2-5A-anti-hTR with adenoviral transfer of the p53 gene has a

signicantly greater antitumor eect for malignant gliomas.266
Other chemically modied derivatives, including 2 0 -deoxy-,
hydroxy-, methoxy-, and uoro-N3 0 P5 0 phosphoramidates,
have been tested as potential therapeutic agents against
telomerase in vitro.267
In addition to oligonucleotides directed against the TERT
mRNA, a ribozyme targeting downstream from the 5 0 end of
hTERT mRNA exhibits telomerase inhibitory activity.268
Ribozyme cleavage of the RNA component of human
telomerase also inhibits telomerase activity.269271 A study
showed that telomerase siRNAs targeted against two
regions of the human telomerases cause ecient inhibition of
telomerase expression (Fig. 11d). Telomerase activity in
cells transfected with siRNAs was reduced 77  3% after
1 day.272
Peptide nucleic acids (PNAs) are modied analogs of DNA
or RNA that possess a neutral amide backbone and bind to
complementary nucleic acids with very high anity. Introduction
of complementary PNAs to telomerase RNA eectively
inhibited telomerase activity, shortened telomeres, and
arrested cancer cell proliferation.273277
6.4 Peptides and proteins
Various chemically synthesized peptides as telomerase-based
drugs were reported. Telomerase is over-expressed in nearly all
cancers, making it an immune target. Multiple approaches to
active telomerase immunotherapy have led to many products
in clinical development.278281 These products involve use of
synthetic TERT peptides or genetic components to prime
antigen-presenting cells. The most advanced products,
GV1001 and GRNVAC1, were designed to stimulate immune
responses to cancer cells. GV1001, a synthetic peptide containing
the 16 amino-acid residues of hTERT protein, is currently in
phase II and III trials in non-small cell lung cancer and
pancreatic cancer,282 and GRNVAC1 is in a phase II trial.283
Other approaches of telomerase inhibition include that
telomerase genes downregulate at the promoter level by the
use of a dominant negative hTERT gene delivery,284 active
telomerase assembly inhibits by interfering with the molecular
chaperones p23 and Hsp90,285287 and telomerase hTR gene
modiers by expressing mutant telomerases.288,289
G-rich telomeric DNA. RecQ, BLM, and WRN helicases also
cooperate with POT1 in the absence of G-quadruplex ligands
to unwind telomere structures of G-quadruplexes.297 In such a
normal condition, G-quadruplexes function as capping
structures. The G-quadruplex stabilization by ligands inhibits
the unwinding of G-quadruplex sequences. It was suggested
that deletions could result from failure to resolve higher-order
structures of G-rich DNA such as G-quadruplex.78 Dierential
activation of the DNA damage machinery should be involved
in the deletion mechanism in the presence of G-quadruplex
ligands.
G-quadruplex structures represent a new class of molecular
targets for DNA-interactive compounds that may be useful to
target telomeres.298300 A large number of ligands reportedly
interact with G-quadruplexes and act as inhibitors of telomerase
activity. NMR and X-ray studies were performed to obtain
detailed information on the interaction of G-quadruplex DNA
with small molecules.
6.6 Pentacyclic acridinium (RHPS4)
A G-quartet end-stacking binding mode was observed in the
NMR structure of a complex between a pentacyclic acridinium
(RHPS4) ligand and the parallel human telomere d(TTAGGGT)4
G-quadruplex (Fig. 12a and b).301,302 The p-system of the drug
overlaps primarily with two bases of each G-tetrad by stacking
interactions with the G-tetrads. Although several exceptions to
this structural feature are known, the requirements shown by
most such ligands seem to be a planar aromatic chromophore
and substituents with terminal basic groups. Several studies
suggest that the ligand inhibits telomerase and induces
telomere uncapping and damage.302311
6.7 Acridine ligand (BRACO-19)
Neidle et al. reported a crystal structure of a complex between
a bimolecular human telomeric G-quadruplex of sequence
d(TAGGGTTAGGGT) and a 3,6,9-trisubstituted acridine
ligand (BRACO-19) (Fig. 13a and b).312 BRACO-19 is a drug
molecule sandwiched between two bimolecular quadruplexes
to form a biological unit, such that the G-quadruplexes are
uniquely stacked 5 0 3 0 . A number of such trisubstituted
acridine analogs, with a variety of side-chain modications
and stereoisomer variations, have exhibited strong

This journal is c The Royal Society of Chemistry 2011 Chem. Soc. Rev., 2011, 40, 27192740 2727

Fig. 12 (a) NMR structure of the complex of RHPS4 (in green)
bound to the tetramolecular G-quadruplex. (b) RHPS4.
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Fig. 13 (a) X-Ray structure of the complex of BRACO-19
(in green) bound to the bimolecular human telomere G-quadruplex.
(b) BRACO-19. (c) Disubstituted triazole-linked compounds.
G-quadruplex binding with accompanying telomerase inhibitory
activity.313325 Recently, a series of disubstituted triazole-
linked acridine compounds was shown to inhibit the activity
of the telomerase enzyme that was found to have selectivity for
human telomeric G-quadruplexes (Fig. 13c).326 Both
lead compounds also have selective inhibitory eects on the
proliferation of cancer cell lines rather than on normal
cell lines.
6.8 Quinacridine analogue (MMQ1)
Teulade-Fichou, Mergny and coworkers reported that
quinacridine analogues have the ability to stabilize
G-quadruplexes.327330 An NMR structure reveals that the
dipropylamino analog MMQ1, a crescent-shaped molecule, is
likely to maximize the overlap with the guanines of the
accessible G-quartet (Fig. 14a and b).331 The NOE cross-peaks
of NMR suggest that the ligand stacks over G-quartets, with
one molecule located at the 5 0 end and the other at the 3 0 end.
In addition to the p-stacking interactions between the ligand
and the G-quartet, the cationic side chains are clearly directed
toward the negatively charged G-quadruplex. A cyclo-
bis-quinacridine BOQ1 with two polyammonium linker
bridges binds signicantly more strongly to G-quadruplexes
than to the monomer compounds (Fig. 14c).332 This selectivity
is attributed to the enhancement of the ligand aromatic surface
2728 Chem. Soc. Rev., 2011, 40, 27192740
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Fig. 14 (a) NMR structure of the complex of MMQ1 (in green)
bound to the (d[T2AG3T])4 tetramolecular G-quadruplex. (b) MMQ1.
(c) Cyclo-bis-quinacridine BOQ1.
in the dimeric structure and the steric hindrance of the
acrocyclic scaold that impedes duplex binding.
6.9 Naphthalene diimide (ND)
A series of tri- and tetrasubstituted naphthalene diimides (ND)
are exceptional G-quadruplex binding agents (Fig. 15), with
melting temperature (Tm) values for the human intramolecular
G-quadruplex that are at least two-fold greater than those of
the acridine compound BRACO19, consistent with telomerase
inhibition.333,334 Both crystalline structures suggested that the
inter- and intramolecular G-quadruplex structures formed with
a naphthalene diimide ligand exhibited ligand-G-quadruplex
end stacking (Fig. 15a and b).335 This arrangement of ligands
and human telomeric G-quadruplexes results in a double
sandwich, in which there are two ligand molecules stacked on
each other to form the boundary between the G-quadruplexes.
Ligands are also bound to the external TTA loop by stacking-
type interactions. Based on the G-quadruplex recognizing
properties of the ND moiety, G-quadruplex ligand/alkylating
dual-functioned molecules were developed by tethering alkylating
agents to the ND core (Fig. 15c).336 It is showed that the
alkylation process occurred preferentially on the G-quadruplex
structure in comparison to other DNA conformations.
Fig. 15 (a) X-Ray structure of the complex of ND (in green) bound
to the d[TAGGG(TTAGGG)3] intramolecular G-quadruplex. (b) ND.
(c) QM5, a G-quadruplex ligand/alkylating dual-functioned molecule.
This journal is c The Royal Society of Chemistry 2011
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Fig. 16 (a) X-Ray crystal structure of TMPyP4 (in green) bound to

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the bimolecular human telomere G-quadruplex. (b) TMPyP4.

(c) Se2SAP. (d) Mn(III)-coordinated porphyrin.

Fig. 17 (a)(f) Telomestatin and the related compounds.

6.10 Porphyrin analogue (TMPyP4)
Porphyrin analogs are well established binding agents for
G-quadruplexes. Hurley et al. have extensively studied the
tetra-N-methyl-4-pyridyl porphyrin (TMPyP4), demonstrating
that the ligand has a high anity for G-quadruplex and
eciently inhibits telomerase (Fig. 16).337345 An X-ray crystal
structure has been imaged of TMPyP4 bound to the bimolecular
human telomere G-quadruplex d(TAGGGTTAGGG)
(Fig. 16a and b).346 An alternative binding mode indicated
that porphyrin molecules bind by stacking on the TTA
nucleotides but without any direct contact with the G-quartets.
The nucleotides in base pairs are involved in the complex,
either as part of the external loop structure or at the 5 0 region
of the stacked G-quadruplex. To enhance the binding selectivity
of G-quadruplex, several porphyrin-like ligands such as
diselenosapphyrin Se2SAP (Fig. 16c),347 Mn(III)-coordinated
porphyrin (Fig. 16d),348 and tetrakis-(diisopropylguanidinio)
zinc phthalocyanine Zn-DIGP349 have been tested for their
ability to interact with the human telomeric G-quadruplex.
These ligands were shown to bind strongly and selectively to
G-quadruplexes. Mn(III)-porphyrin targets the human
telomere G-quadruplex by four orders of magnitude over
duplex DNA.
6.11 Other interactive ligands
A natural product telomestatin targets G-quadruplexes with
high specicity. Telomestatin is one of the most exciting
G-quadruplex ligands extensively studied (Fig. 17a),350359
although there are no structural characterizations of the
binding mode (NMR, X-ray crystallography). It is likely that
a perfect shape adaptation between the macrocycle molecule
and a G-quartet and the hydrophobic forces contribute
to stacking interactions. Its outstanding selectivity for
G-quadruplex and highly promising biological activity encourage
chemists to synthesize a novel class of chemically challenging
telomestatin-like compounds. HXDV354360362 and HXDL363
for example have been found to greatly stabilize the
G-quadruplex structure (Fig. 17b and c). S2A2-6OTD,364
(g) Cyclic oligoamide. (h) Cyclic oxazole-based tripeptide.
L1H1-7OTD (more planar analogue),365 and 6OTD
(dimerisation)366 were shown to interact strongly with
G-quadruplex DNA (Fig. 17df), with a fair quadruplex-
over-duplex DNA selectivity. Other series of macrocyclic
molecules, cyclic oligoamide,367 cyclic oxazole-based
tripeptide (Fig. 17g and h),368,369 and cyclo[n]pyrroles370 have
been investigated as G-quadruplex binding ligands.
Several metal-coordinated ligands have been reported as
potent telomerase inhibitors. The cationic or highly polarized
nature of these ligands is believed to have a major contribution
on the interaction with G-quadruplex DNA. The functionalized
nickel(II)salphen complexes are excellent G-quadruplex DNA
stabilizers (Fig. 18a).371 The Ni2+ ion is possibly playing an
important role for the stability, replacing one of the metal ions
in the channel of the G-quadruplex. A series of platinum(II)
complexes containing dipyridophenazine (dppz) have been
shown to inhibit telomerase activity (Fig. 18b).372 The cationic
Pt(II) complexes containing an extended p-surface are stacked
on the ends of the G-quadruplex. The large p-aromatic
surfaces and positive charges near the center of these mole-
cules increase anity to G-quadruplex. A self-assembled
platinum molecular square [Pt(en)(4,4 0 -dipyridyl)]4 ligand that
is potentially compatible with these features is an ecient
G-quadruplex binder and telomerase inhibitor (Fig. 18c).373
A family of bisquinolinium-substituted derivatives containing
triazines- or pyridine-based core was developed to inhibit
human telomerase activity at low doses (Fig. 19a).374 Furthermore,
replacement of the central cores by a phenanthroline unit
showed to enhance the binding selectivity for intramolecular
human telomere G-quadruplexes (Fig. 19b).375
Recently, Balasubramanian and coworkers developed an
engineered zinc nger protein that binds with high specicity
to the intramolecular G-quadruplex formed by the human
telomeric sequence, and that inhibits the activity of the enzyme
telomerase in vitro.376 A study from the same laboratory
reported that a polyamine-conjugated anthracene ligand

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Fig. 18 (a) Nickel(II)salphen ligands. (b) Platinum(II)-dppz.
(c) [Pt(en)(4,4 0 -dipyridyl)]4 ligand.
Published on 07 February 2011 on http://pubs.rsc.org | doi:10.1039/C0CS00134A
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Fig. 19 (a) Bisquinolinium-substituted triazine 12459.
(b) Phenanthroline-connected bisquinoline. (c) Polyamine-conjugated
anthracene. (d) Chiral cyclic helicene M1.
targeted the central cation channel of the human telomeric
G-quadruplex, a specic structural element in the structure
(Fig. 19c).377 More recently, a chiral cyclic helicene was
suggested to be sandwiched within a chiral-cleft site that was
selectively formed by two human telomere G-quadruplexes,
exhibiting potent inhibitory activity against telomerase
(Fig. 19d).378
6.12 Several novel methods
The perylene diimide, N,N 0 -bis[2-(1-piperidino)-ethyl]3,4,9,10-
perylenetetracarboxylic diimide (PIPER), has been reported to
be selective for human telomere G-quadruplex structures.379
A peryleneEDTAFe(II) ligand as a DNA cleaving unit was
bound to the perylene core of PIPER (Fig. 20a). The conjugate
was shown to selectively cleave G-quadruplex DNA in the
presence of dithiothreitol (DTT).380
A structure based approach was developed to sequence-
specic cleaving of human telomeric DNA by G-quadruplex
formation (Fig. 20b).381 As mentioned above, a dimeric
G-quadruplex can be formed by the three-repeat (16mer)
and single-repeat (6-mer) human telomeric sequences. This
dimeric G-quadruplex structure suggests a way of how a
segment of three G-tracts could bind to a remote G-tract. A
N,N,N 0 ,N 0 -ethylenediamine-tetramethylene-phosphonic acid
(EDTP) as the metal binding group was conjugated to the
16-mer oligonucleotide. The oligonucleotide binds to the
target of human telomere DNA by G-quadruplex formation
and causes a sequence-specic strand break. Formation of a
stable G-quadruplex between the DNAEDTP probe and the
target sequence is a key step in the cleavage reaction. For this
purpose, substitutions of dG in the syn conformation with a
2730 Chem. Soc. Rev., 2011, 40, 27192740
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Fig. 20 (a) PIPER and peryleneEDTAFe(II) ligand. (b) Human
telomere sequence specic cleavage by G-quadruplex-forming
DNAEDTP complex. The structures of EDTP and BrG are shown.
(c) Representation of photo-cross-linking of human telomeric DNA
by a photocontrolled 6-mer oligonucleotide. Structure of a 6-mer
oligonucleotide with a photo-cross-linking reagent, psoralen, at the
5 0 -end.
syn-preferring 8-bromoguanosine (BrG) in the DNAEDTP
probe were performed to form a highly stable G-quadruplex
structure between the probe and target sequence.133,136
Based on the same strategy, a small photocontrolled 6-mer
oligonucleotide was employed to eectively inhibit telomerase
(Fig. 20c).382 Psoralen was selected as a photo-cross-linking
reagent because of its reaction selectivity with pyrimidine
bases. An oligonucleotide bearing psoralen produces a
photoadduct with the telomere target upon irradiation by
G-quadruplex formation. Doses of both psoralen oligonucleotide
and light irradiation trigger death of cancer cells. Because the
main eect on the target is controllable by switching the
light on/o, the small, photocontrolled oligonucleotide can
minimize side eects by irradiation of only cancer cells, which
alleviates the main problem with present-day anticancer
agents.
7. Telomere RNA: a newly emerging player
For a long time, telomeres have been considered transcriptionally
silent, and that their DNA was not transcribed into strands of
RNA. A recent nding demonstrated that telomere DNA is
transcribed into telomeric repeat-containing RNA (referred to
as TERRA) in mammalian cells.383,384 TERRA molecules
This journal is c The Royal Society of Chemistry 2011

were detected in dierent human and rodent cell lines and
contained mainly UUAGGG repeats of heterogeneous length.
These ndings raise the crucial question of how TERRA RNA
is specically associated with chromosome ends. The existence
of TERRA RNA may reveal a new level of regulation and
protection of chromosome ends that could facilitate valuable
insight into fundamental biological processes such as cancer
and aging.385387 Revealing the structure and function of
telomere RNA will be essential for understanding telomere
biology and telomere-related diseases.
7.1 Telomere RNA structure
Published on 07 February 2011 on http://pubs.rsc.org | doi:10.1039/C0CS00134A
To dene the structural features of human telomere RNA
sequence, we examined the conformation of the 12-mer human
telomere RNA sequence r(UAGGGUUAGGGU) in the
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presence of Na+. Multi-method approaches including
circular dichroism (CD), NMR, and gel electrophoresis have
demonstrated that the telomere RNA forms a parallel dimeric
G-quadruplex with external loops similar to the crystalline and
NMR structure of human telomeric DNA (Fig. 21a).388,389
The dimeric RNA G-quadruplex formation was directly
observed by MALDI-TOFMS, suggesting that the RNA
G-quadruplex remains stable even in the gas phase. A human
24-mer telomere RNA sequence r(UUAGGG)4 was also
suggested by CD spectroscopy to form a parallel G-quadruplex
(Fig. 21b).389 The telomere RNA G-quadruplex was found to
induce a strong RNase resistance for UUAGGG repeats
telomere RNA. This nding agrees with the observation
that repeat RNA exists in cells at higher levels and enriches
810-fold in puried polyadenylated RNA compared to total
RNA. The telomere RNA G-quadruplex that resists telomere
RNA degradation may oer a concentration supply of telomere
RNA to participate in essential biological processes.
An NMR-based solution structure suggested a same
folding topology for the 12-mer human telomeric RNA
r(UAGGGUUAGGGU) sequence in K+ solution
390
(Fig. 21a). Terminal U bases stack on the top and the
bottom of the G-tetrad core, respectively. The K+-stabilized
crystal structure of r(UAGGGUUAGGGU) has been
determined to be a parallel G-quadruplex,391 suggesting that
2 0 -OH hydroxyl groups in the RNA quadruplex play a
signicant role in redening the hydration structure in the
grooves and the hydrogen bonding networks.
More recently, we reported the structural features of human
telomere RNA r(UAGGGU) in the presence of K+ and Na+.
It has been demonstrated that a novel U-tetrad is formed at
the 3 0 end of a parallel human telomeric RNA G-quadruplex
(Fig. 21c).392 The U-tetrad dramatically stabilizes the human
telomeric RNA G-quadruplex structure, leading to an increase
in Tm of 29 1C. We noted that four uridine residues located at
the end of the G-quadruple are more favorable for U-tetrad
formation than the dimer telomere RNA G-quadruplex, in
which only two uridine residues are positioned at the ends. The
U-tetrad-stabilized telomeric RNA G-quadruplex structure
adds considerably to our understanding of the diversity of
RNA G-quadruplex architectures.
Telomeric RNA sequences seem to be structural
polymorphisms. This concurs with the NMR study of a 10-mer
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RNA sequence r(GGGUUAGGGU) in K+ solution, which
revealed that two parallel G-quadruplex units assemble via
5 0 5 0 stacking (Fig. 21d).390 This also explains why a 23-mer
telomeric RNA sequence in K+ solution gives unresolved
NMR spectra in the imino proton region. Recently, electro-
spray ionization mass spectrometry (ESI-MS) shows that the
dimers in the longer sequences are stabilized by stacking of
two G-quadruplex subunits (Fig. 21e).393 These observations
are consistent with the models for arrangements of
G-quadruplexes in long human telomeric RNA sequences,
such as a model of alternate-direction stacking of
G-quadruplex blocks (Fig. 21f).111,390,394
It has been shown by CD, NMR, MS, and X-ray crystallo-
graphy that G-rich telomeric RNA sequences are able to form
parallel G-quadruplex structures in Na+ solution as well as in
K+ conditions. However, whether TERRA RNA G-quadruplexes
exist in living cells is unknown. Very recently, we developed a
chemical method to investigate the structural features of
human TERRA RNA in living cells.395 Pyrene was designed
as a light-switching probe. The advantage of the distance
dependence of excimer formation with pyrene can be used as
a unique excimer signaling device for detecting G-quadruplex
structures (Fig. 21g). When the pyrene-labeled probe is free in
solution without G-quadruplex formation, the pyrene
molecules are spatially separated and only the monomer
emission peaks are observed. Formation of G-quadruplex
brings the pyrene molecules at the 5 0 and/or 3 0 ends into close
proximity, allowing the formation of an excimer. The excimer
possesses broad red-shifted emission, in contrast with the
pyrene monomer. The change in emission color serves as a
way to rapidly probe the G-quadruplex structure, and the
excimer uorescence intensity can be used for sensitive
monitoring of G-quadruplex formation. An excimer uorescence
of pyrene (green) is observed in living cells, providing in vivo
evidence of the presence of the G-quadruplex in human
TERRA RNA (Fig. 20h). Co-localized images between probe
and nuclear DNA clearly show that the TERRA RNA
G-quadruplex was restricted to cell nuclei. Furthermore,
TERRA RNA G-quadruplex foci colocalized with TRF2 foci,
indicating that the TERRA RNA G-quadruplex is a common
structural component of mammalian telomeres. Importantly,
the TERRA RNA G-quadruplex was also detected at the ends
of metaphase chromosomes from cells consistent with
previous observations that accumulation of TERRA RNA is
not only in nuclei but also at telomeres.
7.2 Discovery of a telomere DNARNA G-quadruplex by
click chemistry
This discovery of telomere RNA raises the crucial question of
how telomeric RNA is specically associated with telomeric
DNA in terms of chromosome-end regulation and protection.
A possible association between telomere RNA and telomere
DNA may be through the formation of an intermolecular
DNARNA G-quadruplex. It is technically dicult to study the
DNARNA hybrid G-quadruplex structure by traditional
methods, such as NMR spectroscopy and X-ray crystallography,
since the DNA G-quadruplex, RNA G-quadruplex, and
DNARNA hybrid G-quadruplex may coexist as a mixture
Chem. Soc. Rev., 2011, 40, 27192740 2731
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Published on 07 February 2011 on http://pubs.rsc.org | doi:10.1039/C0CS00134A
Downloaded by Pennsylvania State University on 14 May 2012

Fig. 21 (a)(f) Structures of TERRA RNA G-quadruplexes. (g) Schematic for detection of RNA G-quadruplex formation in living cells using a
dual-pyrene probe. (h) Green signals correspond to the probe (green). Cell nuclei were stained with SYTO 25 dye (red). Costaining using antibodies
anti-human TRF2 (in red). Chromosome DNA was stained by propidium iodide (red). (i) Schematic depiction of the detection of the DNARNA
G-quadruplex. The use of 5 0 -azido-labeled DNA and 5 0 -alkyne-labeled RNA may result in a mixture of three types of G-quadruplexes. Only the
DNARNA G-quadruplex brings the alkyne and the azido group into close proximity to give the product of an azidealkyne cycloaddition. (j) and
(k) Higher-order telomeric DNA G-quadruplex, telomeric DNARNA G-quadruplex, TERRA RNA G-quadruplex, and/or t-loop may be
formed at the ends of chromosomes to provide a protective eect.

2732 Chem. Soc. Rev., 2011, 40, 27192740 This journal is c The Royal Society of Chemistry 2011

in solution. Click chemistry has helped overcome this diculty
(Fig. 21i).396 The click reaction can trap a particular species or
produce a snapshot of the various inter-converting structures
that are present in a complex solution. The detected
azido-alkyne cycloaddition product between the 5 0 -alkyne-
labeled RNA and the 50 -azido DNA identies that a DNARNA
hybrid G-quadruplex structure can be formed from human
telomeric DNA and RNA sequences.396
7.3 Telomere RNA function
DNARNA hybrid G-quadruplex structures could inhibit
Published on 07 February 2011 on http://pubs.rsc.org | doi:10.1039/C0CS00134A
telomerase activity by locking telomeric substrate DNA into
an inactive conformation that is no longer recognized or
elongated by the telomerase, consistent with the nding that
telomerase activity is dramatically reduced in the presence
Downloaded by Pennsylvania State University on 14 May 2012
of increased concentrations of telomere RNA in vitro.
Alternatively, through the use of in vitro reconstituted
telomerase and synthetic TERRA molecules, TERRA RNA
has been shown to directly pair with the template region of
hTR as a telomerase ligand and natural direct inhibitor of
human telomerase.397 Lingner et al. proposed three
possible modes for telomerase sequestration by TERRA.
The released TERRA from the telomere may bind and
inhibit telomere-proximal telomerase molecules. Telomere-
bound TERRA may also bind and sequester telomerase and
prevent its access to the telomere. Alternatively, TERRA
may bind to telomeric chromatin bound telomerase and
prevent it from accessing the telomere. Genetic experiments
in Saccharomyces cerevisiae provided evidence that TERRA
regulates telomerase in vivo. TERRA RNA acts as a potent
competitive inhibitor for telomeric DNA in addition to the
intermolecular G-quadruplex mode.
Formation of an intermolecular G-quadruplex by telomeric
RNA and DNA provides a protective eect. Human telomeric
RNA inhibits chromosome end fusions and has an eect on
the inhibition of cellular senescence when TRF2 is inhibited by
inducing a dominant negative allele of TRF2 (TRF2DBD)
(Xu, Y., Ito, K., Katada, H., K, Komiyama, M., submitted
for publication). Human telomeric RNA causes a signicant
increase in the clonogenic capacity of cells after exposure of an
oligonucleotide homologous to the telomere 3 0 -single stranded
overhang (T-oligo), which activates DNA damage signals
and induces cell senescence.398,399 Telomeric DNARNA
G-quadruplexes should avoid the exposure of homologous
single-stranded terminal DNA because it blocks the access of a
key DNA damage regulator(s) to the single stranded DNA.
Consistent with higher-order telomeric DNA G-quadruplex
structures, the telomeric DNARNA G-quadruplex and
TERRA RNA G-quadruplexes may be formed at the terminus
of this superhelix structure to provide a protective
eect (Fig. 21j and k). The consecutive formation of RNA
G-quadruplexes by long TERRA RNA is consistent with a
very recent result that TERRA molecules have an
approximate length of 200 bases.400 In contrast, the lack of
an uncapping structure at the 3 0 -termini of chromosome
ends leads to exposure of the single-stranded terminal DNA
and is recognized by a key DNA damage regulator(s) (ATM),
which activates various DNA damage signals.
This journal is c The Royal Society of Chemistry 2011
View Online
Recent studies indicated that siRNA-mediated depletion
of telomeric RNA caused an increase in telomere dys-
function-induced foci and aberrations in metaphase
telomeres.401,402 Conversely, increased levels of telomeric
RNA observed to be associated with thermal shock, may help
protect telomeres against stress-induced damage.384 Recently,
some proteins have been suggested to be associated with
telomeric RNA,403 such as TRF2, which was found to recruit
telomeric RNA to telomeric DNA.401
8. Conclusions and future prospects
8.1 Structure and function
Telomere biology has come a long way in the past 70 years,
from the observation that chromosomes require protection, to
the award of the 2009 Nobel Prize for the discovery of
telomerase and the eects of telomere shortening on cells.
Functional telomeres have been experimentally implicated in a
number of molecular cell processes. Molecular components of
telomeres, including terminal double- and single-stranded
telomeric DNA, protein complex shelterin, and telomerase
form physical states associated with functional capping and
uncapping.
Telomeric DNA itself has been suggested to form a t-loop
and/or G-quadruplex as a possible cap state. However, key
questions include whether such structures occur in living cells
and, furthermore, what their biological function might be. To
date, whether the two structures exist in living cells is
unknown. Chemistry is expected to oer a powerful approach
to answer this question.
Like t-loops, G-quadruplexes shelter the 3 0 end of the
G-overhang and, although this provides a capping function,
such structures would need to be resolved by telomere
synthesis during replication and telomerase extension. The
two capping structures need not be mutually exclusive, and
could represent dierent functional states. Capping structures
thus may be dynamic in response to cell cycle changes.
What is the molecular basis of the telomeric cap and how do
t-loops and G-quadruplexes contribute to end protection? It is
not clear what the primary signal is that detects uncapped
telomeres, nor is it known how the signal gets translated and
amplied throughout the cell.
What is the role of the many shelterin accessory factors?
Although our understanding of the individual roles of shelter-
in components has improved greatly, much remains to be
discovered about the transcriptional, translational, and post-
translational regulation of these components. Telomeric over-
hang DNA has been suggested to form the higher-order DNA
structures containing consecutive G-quadruplexes. Whether
shelterin components and other proteins bind to such
superhelix structures remains to be elucidated.
In addition, mechanisms of telomere replication remain
poorly dened. It has been suggested that telomere replication
could be regulated by the higher order structures of telomeres.
It is necessary to remove the t-loop and/or G-quadruple
structures that form on the telomere strands, suggesting a
stalling of replication forks at telomeres. Some proteins, such
as RecQ, BLM, WRN and POT1, could be required to resolve
Chem. Soc. Rev., 2011, 40, 27192740 2733
 View Online

G-quadruples.297 The passage of the replication fork through
the telomeric repeats may restart to avoid loss of telomeric
DNA, allowing telomerase and perhaps other enzymes access
to telomeres.
8.2 Drug design
Functional telomeres have been implicated in cancer
progression and aging-related diseases. Although telomere- or
telomerase-based inhibitors work well in vitro and in tissue
culture, they have yet to pass clinical trials. For successful
cancer treatment, several obstacles still have to be overcome.
First, for agents targeting telomere maintenance, a telomerase-
Published on 07 February 2011 on http://pubs.rsc.org | doi:10.1039/C0CS00134A
There is a clear need to revisit the structural and functional
mechanisms of telomeres accompanying telomere RNA
participation. Telomere RNA may be related to telomere
DNA by formation of an intermolecular G-quadruplex,
providing a protective eect. Alternatively, dimerization may
occur on the telomeric RNA G-quadruplex and DNA
G-quadruplex, similar to the dimeric structure formed by
both telomere DNA G-quadruplex and telomere RNA
G-quadruplex units. Stabilization of such structures by small
molecules can lead to telomerase inhibition. This would
transform telomere RNA into a potential target for anti-
cancer agents directed against telomeres.

Telomere RNA, a new player to provide another possible

independent, recombination-based mechanism (ALT) is
answer, may be appropriate to solve the old problem of the
already known to exist in cells.404 Telomeres are typically long
end replication problem. In normal cells, telomere RNA may
and heterogeneous in size in ALT cells. Some studies have
act as a template for telomere elongation synthesis by reverse
investigated potential targets to block recombination-based
Downloaded by Pennsylvania State University on 14 May 2012

transcriptase. Support for this hypothesis comes from the

telomere maintenance.405 In future, a combination of
nding that telomere RNAs are signicantly downregulated
ALT-based drugs and telomerase therapies might be eective.
in various types of human cancers compared to normal tissues.
Second, many gaps might remain in our understanding of
In normal cells, the reverse transcription pathway may be
the complexities of telomere regulation and protection
involved in the maintenance of telomere length, whereas
specicity in telomere-associated DNA repair pathways induced
telomerase is the important enzyme responsible for telomere
by drug treatments. It is clear that DNA repair systems
length maintenance in cancer cells. As indicated by Blasco
eectively counteract the DNA damage in intrachromosomal
et al., the lower telomere RNA production associated with
regions. The number of DNA damage events in a single
carcinogenesis may favor telomerase-mediated telomere
human cell range from 104106 per day, requiring
elongation in cancer cells.384
approximately 10161018 repair events per day in an adult
The recently identied TERRA RNAs that have been
human (1012 cells).406 It is not surprising that strong DNA
shown to interact with TRF2, and the transcription of
repair systems that are further enhanced by participation of
TERRA RNA is bound by a complex set of proteins.403
the telomere-associated proteins can successfully overcome
Whether these proteins or other factors interact with the
DNA damage-induced telomere dysfunction. Chemistry
telomeric RNA G-quadruplex and the DNARNA
should make major contributions in the elucidation of the
G-quadruplex to produce the protective eects remains to be
mechanisms of damage or repair recognition and provides a
discovered. Although TERRA RNA was suggested to not be
combinational approach to both the complex systems and the
translated into proteins, the possibility of its rapid transit
telomere.
through the cytoplasm cannot be excluded. If TERRA RNA
Finally, the structure-based design of telomerase inhibitors
may be translated, the (Arg-Val)n and (Gly-Leu)n poly-
necessitates molecular understanding of the range of
peptides would possibly be generated. Interestingly, the two
G-quadruplex topologies. The conformational diversity of
polypeptides contain similar motifs of G-quadruplex RNA
human telomeric G-quadruplexes introduces design diculties
and RNA-binding domains, arginine, and glycine-rich region
in the specic ligands. A recent example showed a multiple
(RGG box).409,410
target molecule from the higher-order DNA structures
Another possibility is that the process of transcription is
containing consecutive G-quadruplexes. Although any novel
more important than the TERRA RNA itself, similar to
cancer therapeutic always makes arguments, the pre-clinical
several non-coding RNA in that not the RNA itself but the
and emerging clinical experimental evidence for telomerase or
transcription process plays a key role.411 In addition, telomere
telomeres as a target for cancer therapy is encouraging, and
DNA, TERRA RNA, and related-proteins may form TDRP
the targeting of telomere maintenance mechanisms continues
bodies (telomeric DNA, RNA and proteins referred to as
to be an exciting prospect in future cancer strategies.
TDRP), similar to P bodies in mRNA surveillance and mRNA
In contrast, the fact that telomere shortening and telomerase
decay, RNA-mediated silencing and translational control.412
deciency are associated with these human diseases suggested
. . .to understand an end is to understand a beginning of all
that telomerase reactivation and telomere elongation could be
things. . . chemistry ought to make a beginning. . .
an eective way to treat these human disorders. Small circles
of telomeric DNA are being used as templates for rolling-
circle mechanisms of telomerase-independent telomere
elongation.407,408 Chemical approaches can be used to Acknowledgements
engineer articial telomeres on human chromosomes.
This work was partially supported by a Grant-in-Aid for
Scientic Research (B) from the Ministry of Education,
8.3 Telomere RNA
Science, Sports, Culture, and Technology, Japan (22350071),
The nding of telomere RNA molecules opens new doors to and by the Global Centers of Excellence Program for
better understanding of the essential biological role of telomeres. Chemistry Innovation.

2734 Chem. Soc. Rev., 2011, 40, 27192740 This journal is c The Royal Society of Chemistry 2011

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