THE JOURNAL OF BIOLOGICAL CHEMISTRY
Minireview
Regulation and Function of
SUMO Modification*
Published, JBC Papers in Press, September 24, 2004,
DOI 10.1074/jbc.R400021200
Roland S. Hilgarth‡, Lynea A. Murphy‡§,
Hollie S. Skaggs‡§, Donald C. Wilkerson‡,
Hongyan Xing‡, and Kevin D. Sarge‡¶
From the ‡Department of Molecular and Cellular
Biochemistry and §Graduate Center for Toxicology,
University of Kentucky, Lexington, Kentucky 40536
Small ubiquitin-like modifier (SUMO)1 is a protein of 97 amino
acids that is structurally similar to ubiquitin and has been called
by other names including Smt3p, Pmt2p, PIC-1, GMP1, Ubl1, and
Sentrin (1). Like ubiquitin, SUMO has been found to be covalently
attached to certain lysine residues of specific target proteins (2). In
contrast to ubiquitination, however, sumoylation does not promote
the degradation of proteins but instead alters a number of different
functional parameters of proteins, depending on the protein sub-
strate in question. These parameters include but are not limited to
properties such as subcellular localization, protein partnering, and
DNA-binding and/or transactivation functions of transcription fac-
tors (2– 4). The contrast between the functional effects of ubiquiti-
nation and sumoylation is most striking in the case of I␬B, where
sumoylation stabilizes the protein by modifying the same residue
that is ubiquitinated, thereby directly competing with that path-
way (5). This review will focus on the regulation of SUMO modifi-
cation and its role in controlling the functional properties of pro-
teins. The reader is also referred to other excellent reviews on this
topic (2– 4, 6 – 8).
Enzymology and Regulation of SUMO Conjugation
and Deconjugation
Three different ubiquitous SUMO-related proteins have been
identified in mammalian cells, SUMO-1, SUMO-2, and SUMO-3,
with SUMO-2 and SUMO-3 having greater sequence relatedness
with each other than with SUMO-1 (3, 4). Recently a tissue-specific
SUMO-4 has been identified in human kidney with homology to
SUMO-2/3, which raises the possibility that some SUMO proteins
could have tissue-dependent functions (9). SUMO modification oc-
curs on the lysine in the consensus sequence ⌿KXE (where ⌿
represents a hydrophobic amino acid, and X represents any amino
acid) (2, 3). The mechanism involved in maturation and transfer of
SUMO to target substrates is very similar to that seen with ubiq-
uitination and other ubiquitin-like proteins (3, 4). This process
involves four enzymatic steps: maturation, activation, conjugation,
and ligation (Fig. 1). In the first step the SUMO protein is cleaved
by SUMO-specific carboxyl-terminal hydrolase to produce a carbox-
yl-terminal diglycine motif. This process of maturation is identical
with all three mammalian SUMO forms. After maturation, SUMO
proteins are able to be utilized for conjugation to proteins. The
* This minireview will be reprinted in the 2004 Minireview Compendium,
which will be available in January, 2005.
¶ To whom correspondence should be addressed: Dept. of Molecular and
Cellular Biochemistry, University of Kentucky, 800 Rose St., Lexington, KY
40536. Tel.: 859-323-5777; E-mail: kdsarge@uky.edu.
1
The abbreviations used are: SUMO, small ubiquitin-like modifier; E1,
ubiquitin-activating enzyme; E2, ubiquitin carrier protein; E3, ubiquitin-
protein isopeptide ligase; PIAS, protein inhibitors of activated STATs; STAT,
signal transducer and activator of transcription; PML, promyelocytic leuke-
mia; NPC, nuclear pore complex; TGF-␤, transforming growth factor ␤; NB,
nuclear body; AR, androgen receptor; GR, glucocorticoid receptor; PR, pro-
gesterone receptor; C/EBP, CCAAT enhancer-binding protein; SREBP, sterol
regulatory element-binding protein; SRF, serum response factor; HDAC,
histone deacetylase; PCNA, proliferating cell nuclear antigen; EBV, Epstein-
Barr virus; HSF, heat shock factor; TCF, T-cell factor; LEF, lymphoid en-
hancer factor.
This paper is available on line at http://www.jbc.org 53899
Vol. 279, No. 52, Issue of December 24, pp. 53899 –53902, 2004
© 2004 by The American Society for Biochemistry and Molecular Biology, Inc.
Printed in U.S.A.
SUMO-activating (E1) enzyme is a heterodimer consisting of Aos1
and Uba2 (also known as SAE1/SAE2 or Sua1/hUba2 in humans).
Activation of SUMO by the E1 is an ATP-dependent process and
results in the formation of a thioester bond between SUMO and the
Uba2 subunit of the E1-activating enzyme. Activation is followed
by transfer of SUMO from the E1 enzyme to a conserved cysteine in
the conjugating (E2) enzyme, Ubc9. This single E2 enzyme identi-
fied so far for the sumoylation pathway contrasts with the multiple
E2 enzymes involved in attaching ubiquitin to proteins (4, 10).
The final step of sumoylation involves ligation of SUMO to the
target protein. Until recently there was speculation as to whether
SUMO ligation to target proteins involved E3 ligase-like proteins
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such as are required for ubiquitination. However, it is now clear
that such E3 ligases do exist for the SUMO-1 modification pathway
and that they play important roles in modulating the efficiency of
SUMO attachment to target proteins (2). As with the ubiquitin
system, SUMO E3 proteins are defined by three characteristics:
binding to the substrate protein either directly or indirectly, bind-
ing to the E2 conjugation enzyme, and the ability to stimulate
transfer of the modifier to the substrate or to another modifier in
the case of modifier chain formation. Three different general types
of SUMO E3 ligases have been described (11–16). The first E3
group comprises the PIAS family of proteins. In yeast only two E3
proteins have been identified (Siz1 and Siz2) which have sequence
similarity to mammalian PIAS proteins, of which at least five
members have SUMO E3 activity (11, 12, 14, 17). These proteins
share a common RING finger-like structure and bind directly to the
Ubc9 E2 enzyme and some SUMO protein targets. This RING
finger motif has also been identified in some of the ubiquitin E3
ligases (18). A second type of SUMO E3 protein found in mamma-
lian systems is RanBP2, which is part of the nuclear pore complex
(15). RanBP2 differs from the PIAS proteins in that it does not have
a RING finger domain or homology to ubiquitin E3 proteins. How-
ever, it interacts with Ubc9 although not the sumoylation target
protein (15). The final E3 protein type (Pc2) belongs to the Poly-
comb protein family and stimulates sumoylation of C terminus
binding protein (16). In some cases sumoylation can exist in the
form of polymeric chains because the SUMO-1 paralogs SUMO-2
and SUMO-3 have internal SUMO modification consensus sites
that allow the formation of polymeric SUMO chains on modified
proteins (19). Other post-translational modifications can regulate the
SUMO modification of a protein. For example, phosphorylation neg-
atively regulates the sumoylation of several substrate proteins, in-
cluding c-Jun, promyelocytic leukemia (PML), and I␬B␣, (2, 3). Phos-
phorylation can also act positively, as in the case of the transcription
factor HSF1 where sumoylation is stimulated by phosphorylation of
serine residues near the SUMO modification site (20, 21).
As with other post-translational modifications, SUMO groups can
be removed from proteins in a reaction catalyzed by SUMO-specific
proteases (2, 3). Some of these proteases have dual functionality in
that they both process SUMO to its mature diglycine form and also
cleave the isopeptide bond between SUMO and its target proteins (2).
In yeast, two SUMO proteases have been identified, Ulpl and Ulp2/
Smt4, both of which are specific for SUMO and display compartmen-
talization, with Ulp1 being present at the nuclear pore complex and
Upl2/Smt4 being present in the nucleoplasm. In mammals, several
SUMO proteases have been confirmed with the possibility of many
more being present due to alternative splice variants (2). As with
yeast, many of the mammalian SUMO proteases are localized to
different cellular compartments, which may function to regulate the
balance of protein sumoylation in these compartments.
Sumoylation and Subcellular Localization
Depending on the target protein, sumoylation can occur in the
cytoplasm or nucleus, and this modification is involved in regulat-
ing the subcellular localization of a number of substrate proteins.
RanGAP1 was the first identified SUMO substrate and plays an
53900 Minireview: Regulation and Function of SUMO Modification
FIG. 1. The SUMO conjugation pathway. SUMO is cleaved into its
mature form by the SUMO protease Ulp1. After this step it is activated in an
ATP-dependent manner by conjugation to the Uba2 subunit of the E1-
activating heterodimer Aos1/Uba2. Following activation SUMO is trans-
ferred to the E2-conjugating enzyme Ubc9. In the final step SUMO is trans-
ferred in a ligation reaction to substrate proteins forming an isopeptide bond
between the terminal glycine on SUMO and the ⑀-amino group of a lysine in
the target protein to be modified. This ligation reaction is aided by SUMO
ligase E3 proteins (E3), which can directly interact with target proteins or
the E2 enzyme.
important role in the regulation of transport of ribonucleoproteins
and proteins across the NPC (22, 23). Unmodified RanGAP1 re-
sides predominantly in the cytoplasm and upon conjugation with
SUMO associates with the cytoplasmic fibers of the NPC (22, 24).
SUMO modification directs RanGAP1 to the NPC by an interaction
with RanBP2/Nup358, possibly mediated by sumoylation-induced
formation of a binding interface for interaction of these two pro-
teins (25). Analysis of nuclear localization signal mutants of a
protein called Smad4, a factor with a major role in the TGF-␤ signal
transduction pathway, indicates that nuclear import of this protein
is required for it to be sumoylated (26). Smad4 moves to the nucleus
in response to TGF-␤ stimulation, and immunofluorescence analy-
sis of TGF-␤-induced cells that were SUMO-1 transfected demon-
strated an increase in the nuclear localization of Smad4 (26).
Nuclei contain a number of distinct bodies that are defined, at
least in part, by the proteins contained in them. For example, the
PML and Sp100 proteins are major components of PML nuclear
bodies (PML NBs), also called ND10. Sumoylation has been found
to be required for the subcellular localization of some, but not all,
proteins found in bodies such as ND10. For example, the sumoylated
forms of PML and Sp100 are found exclusively in the nucleus (27).
SUMO conjugation was determined to be essential for PML protein
localization in ND10, whereas the targeting and accumulation of
Sp100 in these bodies was not sumoylation-dependent (27, 28). This
appears to be true for other SUMO substrates as well (p53, LEF1,
Daxx, and SRF1) which will localize to ND10 even after mutation of
their target lysine (3). Topors, a DNA topoisomerase I-binding pro-
tein, interacts with both Ubc9 and SUMO-1 leading to the formation
of Topors nuclear speckles with close association to ND10, although
sumoylation-deficient mutants were still able to localize to the nu-
clear speckles (29). SUMO modification also targets cellular localiza-
tion of tumor suppressors TEL and Smad4, which in the case of TEL,
a suspected tumor suppressor, leads to localization of this phospho-
protein in TEL bodies, a cell cycle-dependent nuclear structure (30).
Sumoylation appears to also be important for localization of the
transcription factor HSF1 to nuclear bodies (31).
An exciting development in understanding both the subcellular
sites of sumoylation and the role of this modification in regulating
subcellular localization of proteins has been the discovery that
components of the sumoylation machinery are localized at the
nuclear pore complex (32, 33). This localization suggests that
sumoylation of at least some proteins occurring as they enter the
nucleus could be involved in nuclear import itself or perhaps re-
tention of these proteins in the nucleus. For example, Nup358, a
nuclear pore protein demonstrated to have SUMO E3 ligase activ-
ity, localizes predominantly to the cytoplasmic filaments of the
NPC and regulates targeting of RanGAP1 to the NPC (2, 25). Other
SUMO enzymes, Ubc9 and SENP2, have also been found to localize
at the nuclear pore. Ubc9, the E2 conjugating enzyme for SUMO,
localizes to the cytoplasmic and nucleoplasmic faces of the NPC as
visualized by immunogold analysis of the nuclear envelope (32).
Ubc9 interacts with Nup358 as well as RanGAP1/SUMO-1, and a
model has been proposed in which these three proteins interact to
form a stable trimeric complex (15, 32). This model is strengthened
by the observation that RanGAP1 is protected from SENP2 (SUMO
protease) degradation when found in this complex (15, 32). SENP2/
Axam itself associates with the nucleoplasmic face of the NPC via
its NH2-terminal domain (32, 34), and loss of this domain results in
relocalization of this enyzme and increased capacity for deconjuga-
tion of substrates (34). SENP2 also associates with Nup153, a
component of the nuclear basket in humans. Ulp1, the yeast ho-
mologue of the vertebrate SUMO isopeptidase SENP2, is required
for progression through the cell cycle and also localizes to the NPC
via the NH2-terminal domain, which appears to be necessary for
localization as well as enzymatic specificity (35). Further establish-
ing the connection between sumoylation and nuclear import are
data showing that yeast Ulp1 and Ulp2 mutants, deficient in
SUMO conjugation, display an impairment of classical nuclear
localization signal-mediated protein import (36).
Sumoylation is most often implicated in promoting localization
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of proteins to the nucleus and in some cases to nuclear bodies.
However, there is evidence that SUMO modification could also
function to regulate nuclear export of some substrates. For exam-
ple, nuclear sumoylation of Dictyostelium Mek1 is responsible for
its movement to the cytoplasm (37), and mutation of lysine 99 of the
TEL protein leads to increased levels of this protein in the nucleus,
suggesting a possible role for sumoylation in its nuclear export (38).
In addition, sumoylation of heterogeneous nuclear ribonucleopro-
teins M and C has been proposed to function as a regulator of
conformational changes that may influence nucleocytoplasmic
transport of these protein complexes (39).
SUMO and Transcription Regulation
The sumoylation of transcription activators, repressors, coacti-
vators, corepressors, and components of PML NBs is involved in
the regulation of gene expression (3, 6, 8). The activities of many
transcription factors are regulated by association with PML NBs,
and assembly of PML NBs requires sumoylation of the PML pro-
tein (3, 7). Thus, alteration of PML sumoylation has broad effects
on transcription (1, 7). For example, sumoylation of PML recruits
corepressor Daxx to PML NBs, thereby relieving Daxx-mediated
repression of these genes. Similarly, sumoylation of PML directs
p53 to PML NBs and could then trigger some modification, such as
acetylation and sumoylation, which stimulates the transcriptional
activity of p53. Also, sumoylation of PML recruits another sumoyl-
ated nuclear body-associated protein, Sp100. Sumoylation of other
transcription factors has also been found to regulate their localiza-
tion, including Drosophila Dorsal, Bicoid, p73␣, and Pdx1 (1). Sim-
ilar to what is observed for PML, corepressor HIPK2 and repressor
TEL and TEL-AML1 localize to nuclear dots in a SUMO-dependent
manner. Whether sumoylation alters the repressive function of
these transcription factors is unclear.
The sumoylation of transcription factors has been reported to
have different effects on their activities in various pathways in-
cluding those involving cytokines, WNT, steroid hormone, and
AP-1 (3, 6, 8). In most cases, SUMO modification plays a negative
role in transcription regulation. The transcription factors that are
inhibited by SUMO modification include STAT1, catenin-TCF/
LEF, c-Jun, Ah receptor nuclear translocator (ARNT), CEBP␣,
c-Myb, Sp3, IRF-1, SREBPs, SRF, Elk, AP1, AP2, androgen recep-
tor (AR), glucocorticoid receptor (GR), and progesterone receptor
(PR), as well as huntingtin (3, 6, 40). The ⌿KXE sumoylation site
motifs of some factors such as GR, Sp3, c-Myb, C/EBP, and the
SREBPs are located within an inhibitory or negative regulatory
domain or the so-called “synergy control” motifs that can transre-
press transcriptional activity. Mutation of sumoylation sites in
transcription factors has been found to increase their transcrip-
tional activity, for example, transcription factors Elk-1, Sp-3,
SREBPs, STAT-1, SRF, c-Myb, C/EBPs, AR, p300, c-Jun, GR, and
peroxisome proliferator-activated receptor ␥ that may reflect a role
for SUMO-1 modification as a negative regulator of transactivation
domains (3, 6, 41). Consistent with this idea, overexpression of free
SUMO-1 can suppress AP2 and AP2-mediated transcription (8).
Direct evidence for repression of transcriptional activity by sumoy-
lation is that fusion of SUMO to GAL4 drastically reduces its
activity in reporter gene assays (42). Furthermore, SUMO is also
 Minireview: Regulation and Function of SUMO Modification
able to inhibit transcription in trans as demonstrated by SUMO-
dependent trans-repression of the VP-16 activation domain (43).
The effects of SUMO on transcriptional activity may be compli-
cated by the finding that a number of transcription co-factors, such
as GRIP1, SRC-1, and histone deacetylases (HDAC) 1 and 4, are
also sumoylated (1, 3, 6, 8). Sumoylation might be involved in
modulating the functions of proteins as co-activators (GRIP1,
SRC-1) or co-repressors (HDAC1, HDAC4) but is not essential (8).
Several observations reveal that the PIAS/SUMO system may mod-
ulate the assembly of coactivator or corepressor complexes that
regulate transcription (40). Other findings indicate further links
between the SUMO system and class I and class II HDACs that
mediate transcription repression. For example, sumoylation of
p300 can mediate repression of gene activity by recruitment of the
corepressor HDAC6 (44). The AR, which interacts with the core-
pressor SMRT, is part of a larger HDAC1-containing complex (45).
Mutation of the sumoylation site in AR abrogates SMRT binding,
suggesting that sumoylation is required for the association of
SMRT and class 1 HDACs. Similar data show that histone H4
sumoylation mediates transcriptional repression through recruit-
ment of HDAC1 and HP1 (46). However, sumoylation of methyl-
transferase 3a (Dnmt3a) disrupts its ability to interact with
HDAC1/2, which abolishes its capacity to repress transcription
(47). Regarding other possible mechanisms by which sumoylation
could mediate effects on transcription factors/co-factors, examples
where sumoylation has been found to regulate ubiquitination of
proteins such as NF␬B inhibitor I␬B␣, PCNA, Smad4, and Mdm2,
either directly by competition for the modified lysine or indirectly,
leaves open the possibility that some effects of sumoylation could
be mediated via control of protein levels in general or turnover of
specific subpopulations of a protein in a cell (3, 6, 48).
Although sumoylation of most transcription factors results in
repression, SUMO modification appears to have positive effects on
transcriptional activation by the heat shock factors HSF1 and
HSF2 and the ␤-catenin-activated factor Tcf-4. Sumoylation of
HSF1 and HSF2, which is stress-induced in the case of HSF1 but
can be observed for HSF2 present in non-stressed cells, is corre-
lated with their localization to PML NBs (31, 49). For both HSFs,
in vitro sumoylation leads to increased DNA-binding activity, but
in the case of HSF1, mutation of the sumoylation site did not
appear to block stress-induced DNA-binding activity in cells (21,
31, 49). One possibility is that, because of the critical importance of
inducing heat shock protein expression in response to cellular stress,
cells may have evolved multiple independent pathways for activating
HSF1 DNA binding, of which sumoylation is only one. Tcf-4-depend-
ent transcription is activated by coexpression of ␤-catenin and PIASy,
and this activation is reduced when Tcf-4 lacks SUMO attachment
sites, suggesting that sumoylation activates Tcf-4 (50). A protein
called DJ-1, originally identified as a Myc-interacting protein, posi-
tively regulates AR activity and also appears to be modified by
SUMO, and mutation of the acceptor lysine destroys the capacity of
DJ-1 to positively regulate AR activity (13).
Role of SUMO in Genomic Integrity and Chromosomes
Since its discovery, sumoylation has held an important role in
cell biology that extends into fields such as chromosome cohesion
and kinetochore assembly. During mitosis, the proper distribution
of chromosomes into replicated cells is a highly ordered and com-
plex process that is dependent upon the proper timing of sister
chromatid assembly and separation. Misregulation of this process
was one of the first phenotypes described in SUMO-1 (Smt3/Pmt3)
mutants in yeast, characterized by aberrant mitosis and defects in
chromosomal segregation (51, 52). Other components of the sumoy-
lation machinery, such as the E2 conjugating enzyme and SUMO
isopeptidases, have also been shown to be important for this proc-
ess. For example, the SUMO-1 isopeptidase in budding yeast
(Smt4) acts as a key regulator of centromeric chromatid cohesion
(53). The same study also suggested that the yeast homologue of
topoisomerase II (Top2) was the SUMO-1 substrate important for
this process, because topoisomerase II mutants lacking SUMO-1
modifications sites can rescue defects in the isopeptidase mutants
(53). In support of this idea, topoisomerase II was found to be the
major high molecular weight, chromatin-dependent sumoylated
protein in mitotic Xenopus extracts (54). Interestingly, this effect
53901
does not appear to be mediated via sumoylation-induced changes in
topoisomerase II activity, because a dominant negative mutation in
the Ubc9 (SUMO E2 conjugation enzyme) prevented sister chro-
matid cohesion at the metaphase to anaphase transition but did
not alter topoisomerase II activity (54). Sumoylation of other pro-
teins such as the Psds5 protein has also been implicated in sister
chromatid cohesion. In the case of Psds5, which is a non-essential
regulator of cohesion maintenance in yeast, results suggest that
the desumoylation of this protein promotes sister chromatid disso-
lution by rendering the cohesin complex, which acts as the molec-
ular glue between sister chromatids, accessible to other factors that
promote dissolution (55).
The role of SUMO-1 in mitotic chromosome structure is not
limited to the cohesive properties of centromeres, as sumoylation
has also been implicated in the maintenance and recruitment of
proteins to the kinetochore, the protein complex that forms at the
centromere and recruits microtubules for anaphase separation. In
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Saccharomyces cerevisiae, SUMO-1 has been shown to be a sup-
pressor of a temperature-sensitive MIF2 (yeast homologue of
CENP-C), a protein which links ␣-satellite-containing centromeric
DNA to the proteins of the inner kinetochore plate (56). Interest-
ingly, neither CENP-C nor MIF2 is sumoylated, and thus the role
of sumoylation is thought to be indirect (57). In addition to modi-
fying several central kinetochore/centromere proteins, sumoylation
is also thought to target various proteins to this region during
mitosis for reasons which remain unclear. For example, during
mitosis SUMO-1 targets RanGAP1 to the mitotic spindles and
kinetochores, and at the kinetochores specifically, RanBP2/Nup358
colocalizes specifically at the kinetochore (58).
In addition to the apparent role of sumoylation in chromosome
maintenance and kinetochore assembly/disassembly, the sumoyla-
tion modification of a number of critical tumor suppressor and
repair proteins implicated SUMO-1 as an integral player in main-
taining genomic stability. p53 and Mdm2 are both targets of
sumoylation, which has functional effects on the activities of these
proteins (3, 6, 7, 48). Evidence indicates that components of the
Wnt signaling cascade (e.g. axin, ␤-catenin, LEF/Tcf-4) are also
targets of sumoylation, which may regulate the system at multiple
vertical and horizontal steps (3, 6, 7). Although sumoylation ap-
parently affects cell cycle and developmental proteins, the integrity
of DNA itself may also rely on the sumoylation status of various
proteins, particularly those involved in DNA repair. Both UBL1
(SUMO-1) and UBE2I (Ubc9) have been identified to interact with
RAD51/52, proteins well known for their role in homologous recom-
bination and repairing double-stranded breaks in cells (59, 60).
Sumoylation has also been implicated in the repair of the DNA
damage mediated by topoisomerase II (61, 62), which is of clinical
relevance because topoisomerase is a target of numerous anti-cancer
therapies. More recent evidence suggests that the Rad6 postreplica-
tive repair pathway is apparently sumoylation-dependent, particu-
larly with respect to PCNA, the activity of which varies by which
molecular tag (e.g. SUMO-1 or ubiquitin) it carries (63, 64). The
balance between sumoylation and ubiquitination of PCNA, which
determines which specific repair pathway the cell utilizes, illustrates
the critical role of sumoylation in this important cell function.
SUMO and Viral Proteins
Two major-immediate-early (MIE) proteins critical for propaga-
tion of the human cytomegalovirus and herpesvirus, IE1 (IE1-p72
or IE72) and IE2 (IE2-p86 or IE86), have been found to be sumo-
ylated. In the case of the IE1 protein, which is known to interact
with PML, blocking this modification does not disrupt targeting of
this protein to ND10 nuclear bodies nor does it affect ND10 orga-
nization, suggesting that sumoylation is not a prerequisite for the
derepressive activities of IE1 (65, 66). However, IE1 does modulate
the sumoylation of PML and is important for effects on nuclear
body dynamics (67). Targeting of IE2 to ND10 is not affected by
mutations of its target lysine residues, but sumoylation appears to
be critical for IE2-mediated transactivation (68). Recent studies
have also shown that PIAS1 can increase the levels of IE2 sumoyl-
ation which leads to enhanced IE2-mediated transactivation (69).
The BZLF1 (Z) protein of Epstein-Barr virus (EBV) is SUMO-1-
modified at lysine 12 within the transactivation domain, and re-
sults suggest that BZLF1 sumoylation decreases PML SUMO mod-
53902 Minireview: Regulation and Function of SUMO Modification
ification by competing for limiting amounts of free SUMO protein
(70). The immediate early protein E1 of bovine papillomavirus was
found to interact both in vivo and in vitro with Ubc9 using a yeast
two-hybrid screen and to be sumoylated at lysine residue 514 (71).
Mutations within E1 that prevent SUMO-1 modification do not
affect intracellular stability but do disrupt nuclear import and
accumulation leading to the decreased ability of E1 to replicate the
viral genome (71, 72).
A number of adenoviral proteins important for viral replication
have also been shown to be sumoylated. Adenoviral E1B is modi-
fied at SUMO-1 at lysine 104, which is important for the ability of
this protein to transform primary cells and inhibit p53-mediated
transactivation, and also appears to mediate E1B localization to
the nucleus (73). Expression of adenoviral Gam1 leads to a global
reduction in sumoylation including the reduced sumoylation of
HDAC1, dispersal of PML-containing nuclear bodies, and delocaliza-
tion of SUMO-1 (74). The adenovirus E1A protein has been shown to
physically interact with the SUMO E2 Ubc9 protein although no
clear role has been identified (75). In addition, yeast two-hybrid
analysis indicated that the geminivirus TYLCSV protein Rep inter-
acts with a Ubc9 homologue from Nicotiana benthamiana (NbSCE1),
but it is not clear if Rep is a substrate for sumoylation (76).
Perspectives
Investigation of the regulation and function of SUMO modifica-
tion of proteins is an exciting and rapidly growing field. The recent
use of broad proteomics approaches to identify large numbers of
new putative sumoylated proteins will only add to the already
rapid pace of advance (77– 81). Key areas requiring further inves-
tigation include understanding the underlying molecular and bio-
chemical mechanisms by which this modification plays its critical
roles in regulating subcellular localization, transcription, chromo-
some function, and genomic integrity, to name a few, and to un-
derstand how sumoylation leads to different effects in different
proteins. Further investigation of the mechanisms and function of
nuclear pore-associated sumoylation, including identification of ad-
ditional proteins that are sumoylated at this cellular site, should
also yield interesting new results and better understanding of the
role of this important protein modification.
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