DNA Repair and Cancer

DNA Damage

Endogenous DNA replication errors

VDJ recombination
aldehydes
ROS

Exogenous IR, UV, radioisotopes, natural

and contaminant
chemicals in diet and air
DNA damage sensed leading to activation of
downstream pathways
DNA damage repair pathways

1. Nucleotide excision repair

2. Base excision repair
3. Mismatch repair
4. Double strand break repair
Nucleotide excision repair (NER)
Human syndromes with defects in NER genes

• Xeroderma pigmentosum
• 1000 fold increase in skin cancer risk
• complementation groups XP-A – XP-G
• Cockayne syndrome
• Trichothiodystrophy
Base excision repair
Mismatch repair
 DNA double strand breaks

ATM

P
p53, Chk2 H2AX, NBS1, BRCA1

Cell cycle arrest DNA repair

Predominant, but not exclusive, dsb repair
pathways depending on stage of cell cycle

G2 G1

HR NHEJ

S
Non-homologous end-joining (NHEJ) repair
pathway for repair of DNA dsb breaks

Artemis
Chromosome aberrations visualised as colour-
junctions which in turn indicate position of dsb
Chromosome rearrangement forms oncogene
between NTRK1 and TPR in thyroid cells

TPR (red) and NTRK1

(green) signals in
PBL (A)
Thyroid (B) interphase nuclei

Rocatto et al
Consequences of mutations in NHEJ
repair genes
Dsb repair by homologous recombination
Consequences of mutations in HR repair genes
 DNA repair and Cancer

• repair defects = extreme variations in very small

proportion of population

• ? Relationship between varying repair capacity

and cancer incidence in whole population

• Impact of this on developing cancer and also on

efficacy of treatment of that cancer
 References

Roccato et al. Cancer Research (2005) 65, 2572-2576

Roix et al. Nature Genetics  (2003) 34, 287 - 291
Kuhne et al. Radiation Protection Dosimetry (2002) 99 129-132
Anderson et al. Cytogenetic and Genome Research (2006) 112
35-44
Rothkamm et al Cancer Research (2001) 61 3886-3893
O'Driscoll and Jeggo. Nature Reviews Genetics (2006) 7, 45-54
Volker et al. Molecular Cell (2001) 8 213-224
Jiricny and Nystrom-Lahti Current Opinion in Genetic
Development (2000) 10 157 - 161