PALB2 chromatin recruitment restores homologous recombination in BRCA1-deficient cells depleted of 53BP1

• Published in: Nature communications 2020-02, Vol.11 (1), p.819-11, Article 819
• Main Authors: Belotserkovskaya, Rimma, Raga Gil, Elisenda, Lawrence, Nicola, Butler, Richard, Clifford, Gillian, Wilson, Marcus D., Jackson, Stephen P.
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/106; 13/109; 13/89; 14/19; 14/35; 14/63; 38/22; 38/23; 42; 42/41; 42/70; 49/31; 631/337/1427/2190; 631/80/2373; 82/16; 82/29; 82/80; 82/83; Adenosine diphosphate; Amino Acid Motifs; BRCA1 protein; BRCA1 Protein - deficiency; BRCA2 protein; BRCA2 Protein - deficiency; Breast cancer; Cell Line; Chromatin; Chromatin - metabolism; Defects; Deoxyribonucleic acid; Depletion; DNA; DNA Breaks, Double-Stranded; DNA damage; DNA repair; DNA Repair - genetics; Double-strand break repair; Drug resistance; Fanconi Anemia Complementation Group N Protein - chemistry; Fanconi Anemia Complementation Group N Protein - deficiency; Fanconi Anemia Complementation Group N Protein - genetics; Fanconi Anemia Complementation Group N Protein - metabolism; Filaments; Homologous Recombination; Homology; Humanities and Social Sciences; Humans; Inhibitors; multidisciplinary; Mutants; Nucleosomes - metabolism; Null cells; Poly(ADP-ribose) polymerase; Recruitment; Repair; Ribose; Science; Science (multidisciplinary); Tumor Suppressor p53-Binding Protein 1 - deficiency; Ubiquitin; Yeast
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-14563-y

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. Although loss of BRCA1 leads to defects in DNA double-strand break repair by homologous recombination (HR) and renders cells hypersensitive to PARP inhibitors, resistance to the drugs can arise. Here the authors reveal that PALB2 chromatin recruitment restores HR in BRCA1-deficient cells depleted of 53BP1.