palb2 chromatin recruitment restores homologous recombination in brca1 deficient cells depleted of 53bp1

• DOI: 10.17863/cam.64495
• Publication Date: 2020-02-10
• Authors: Stephen P. Jackson; Marcus D. Wilson; Gillian Clifford; Elisenda Raga Gil; Elisenda Raga Gil; Nicola Lawrence; Richard Butler; Rimma Belotserkov...
• Keywords: 570; /82/29; DNA Repair; Science; Amino Acid Motifs; 610; /13/106; /13/109; Cellular imaging; /13; Article; Cell Line; /82/80; /13/1; name=General Biochemistry,Genetics and Molecular Biology; /38/23; /38/22; /42/41; Humans; DNA Breaks, Double-Stranded; Homologous recombination; /14/19; Homologous Recombination; /14/35; /13/89; /82/83; /631/80/2373; /49/31; /42; BRCA2 Protein; /dk/atira/pure/subjectarea/asjc/1300/1300; /82/16; BRCA1 Protein; Q; article; Chromatin; Nucleosomes; name=General Physics and Astronomy; /631/337/1427/2190; /14/63; /dk/atira/pure/subjectarea/asjc/3100/3100; /42/70; Fanconi Anemia Complementation Group N Protein; Tumor Suppressor p53-Binding Protein 1; name=General Chemistry; /dk/atira/pure/subjectarea/asjc/1600/1600

AbstractLoss 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.