Table of Contents
DNA repair defects in cancer #
At least 8 distinct DNA repair pathways
- DNA mismatch repair (MMR)
- Base excision repair (BER)
- Nucleotide excision repair (NER)
- Translesion synthesis (TLS)
- Homologous recombination (HR)
- Non-homologous end joining (NHEJ)
- Fanconi anemia (FA)
- O6-methylation DNA methyltransferase (MGMT)
Genome instability and cancer #
Exploiting genomic aberrations for targeted cancer therapy #
Synthetic lethality between HR and PARP1 inhibition #
PARP1 promotes HR at stalled and/or collapsed replication forks as opposed to resolving DSBs per se by HR or classic NHEJ. Lastly, PARP1 was shown to be involved in an alternative NHEJ pathway (A-NHEJ).
PARP1 inhibition led to the induction of DNA damage in both BRCA1/2- proficient and -deficient cells. Intriguingly, BRCA1/2- defective cells were exquisitely sensitive to PARP1 inhibition, whereas BRCA1/2-proficient cells were resistant.