PALB2 chromatin recruitment restores homologous recombination in BRCA1-deficient cells depleted of 53BP1.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 32041954.
- Also identified by DOI 10.1038/s41467-020-14563-y and PMC identifier 7010753.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Loss of functional BRCA1 protein leads to defects in DNA double-strand break (DSB) repair by homologous recombination (HR) and renders cells hypersensitive to poly (ADP-ribose) polymerase (PARP) inhibitors used to treat BRCA1/2-deficient cancers. However, upon chronic treatment of BRCA1-mutant cells with PARP inhibitors, resistant clones can arise via several mechanisms, including loss of 53BP1 or its downstream co-factors. Defects in the 53BP1 axis partially restore the ability of a BRCA1-deficient cell to form RAD51 filaments at resected DSBs in a PALB2- and BRCA2-dependent manner, and thereby repair DSBs by HR. Here we show that depleting 53BP1 in BRCA1-null cells restores PALB2 accrual at resected DSBs. Moreover, we demonstrate that PALB2 DSB recruitment in BRCA1/53BP1-deficient cells is mediated by an interaction between PALB2's chromatin associated motif (ChAM) and the nucleosome acidic patch region, which in 53BP1-expressing cells is bound by 53BP1's ubiquitin-directed recruitment (UDR) domain.
Medical subject headings
- BRCA1 Protein
- Chromatin
- Fanconi Anemia Complementation Group N Protein
- Homologous Recombination
- Tumor Suppressor p53-Binding Protein 1