Faculty Opinions recommendation of BRCA1 Haploinsufficiency Is Masked by RNF168-Mediated Chromatin Ubiquitylation.
Year: 2019
Type: peer-review
Abstract: BRCA1 functions at two distinct steps during homologous recombination (HR).Initially, it promotes DNA end resection, and subsequently recruits the PALB2 and BRCA2 mediator complex, which stabilizes RAD51-DNA nucleoprotein filaments.Loss of 53BP1 rescues the HR defect in BRCA1 deficient cells by increasing resection, suggesting that BRCA1's downstream role in RAD51 loading is dispensable when 53BP1 is absent.Here, we show that the E3 ubiquitin ligase RNF168, in addition to its canonical role in inhibiting end resection, acts in a redundant manner with BRCA1 to load PALB2 onto damaged DNA.Loss of RNF168 negates the synthetic rescue of BRCA1 deficiency by 53BP1 deletion and predisposes BRCA1 heterozygous mice to cancer.BRCA1 +/-RNF168 -/-cells lack RAD51 foci and are hypersensitive to PARP inhibitor, while forced targeting of PALB2 to DNA breaks in mutant cells circumvents BRCA1
Author: Lee Zou
Institutions: Harvard University, Massachusetts General Hospital
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W4252002890