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

Rimma Belotserkovskaya (Lead / Corresponding author), Elisenda Raga Gil, Nicola Lawrence, Richard Butler, Gillian Clifford, Marcus D. Wilson (Lead / Corresponding author), Stephen P. Jackson (Lead / Corresponding author)

Research output: Contribution to journalArticle

16 Downloads (Pure)

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.

Original languageEnglish
Article number819
Pages (from-to)1-11
Number of pages11
JournalNature Communications
Volume11
Issue number1
DOIs
Publication statusPublished - 10 Feb 2020

    Fingerprint

Keywords

  • Cellular imaging
  • Homologous recombination

Cite this

Belotserkovskaya, R., Raga Gil, E., Lawrence, N., Butler, R., Clifford, G., Wilson, M. D., & Jackson, S. P. (2020). PALB2 chromatin recruitment restores homologous recombination in BRCA1-deficient cells depleted of 53BP1. Nature Communications, 11(1), 1-11. [819]. https://doi.org/10.1038/s41467-020-14563-y