Cancer-specific defects in DNA repair pathways as targets for personalized therapeutic approaches
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- (rev. 5)
- Hyungyong Kim
Structured data
- About
- DNA repair
- Cancer genomics
- Date Published
- Publisher
- Trends in Genetics
- URL
- http://www.cell.com/trends/genetics/abstract/S0168-9525(14)00096-1
Table of Contents
Summary #
Introduction #
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 #
Oncogene addiction
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).
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 #
ATM과 PRKDC가 Synthetic 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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