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Cancer-specific defects in DNA repair pathways as targets for personalized therapeutic approaches #
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Summary #

Introduction #

DNA repair defects in cancer #

At least 8 distinct DNA repair pathways

  1. DNA mismatch repair (MMR)
  2. Base excision repair (BER)
  3. Nucleotide excision repair (NER)
  4. Translesion synthesis (TLS)
  5. Homologous recombination (HR)
  6. Non-homologous end joining (NHEJ)
  7. Fanconi anemia (FA)
  8. O6-methylation DNA methyltransferase (MGMT)

Genome instability and cancer #

Exploiting genomic aberrations for targeted cancer therapy #

Oncogene addiction

Synthetic lethality between HR and PARP1 inhibition #

PARP1BER 관련됨. 그리고, HR에도.

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).

PARP1의 저해가 BRCA1/BRCA2 defective cell에 민감하게 반응한다.

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.

Synthetic lethality between HR and NHEJ #

ATMPRKDCSynthetic lethality 관계가 있다. PRKDC 단백질이 DNA-PKcs이며, ATM deficient cell에 DNA-PKcs 저해제가 효과가 있다.

HR deficient cell과 proficient cell에 각각 DNA-PKcs inhibitor를 처리하면, dificient는 HR도 못하고, NHEJ도 못하고 사망

What is the functional relevance of exon 1 mutations in MSH3? #

At which step of the HR process is Msh3 involved? #

Genes with multifunctional roles in distinct DNA repair pathways define signaling hubs that are frequently inactivated in cancer #

Towards the clinic – designing mechanism-guided combination therapies #

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