Dna Repair And Cancer

DNA Repair and Cancer

DNA Damage

Endogenous

DNA replication errors VDJ recombination aldehydes ROS

Exogenous

IR, UV, radioisotopes, natural and contaminant diet and air

chemicals in

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

p53, Chk2 Cell cycle arrest

P

H2AX, NBS1, BRCA1 DNA repair

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

G1

G2

HR

NHEJ S

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

Artemis

Chromosome aberrations visualised as colourjunctions 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