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

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Belotserkovskaya, Rimma  ORCID logo
Raga Gil, Elisenda 
Butler, Richard 
Clifford, Gillian 

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.

Article, /631/80/2373, /631/337/1427/2190, /13, /13/1, /14/19, /38/22, /38/23, /14/63, /14/35, /13/89, /13/106, /49/31, /82/16, /82/29, /82/80, /82/83, /13/109, /42, /42/70, /42/41, article
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Nature Communications
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Nature Publishing Group UK
Cancer Research UK (CRUK) (C6/A18796)