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

Author

Listed:
  • Rimma Belotserkovskaya

    (University of Cambridge
    University of Cambridge)

  • Elisenda Raga Gil

    (University of Cambridge
    University of Cambridge
    University of Dundee)

  • Nicola Lawrence

    (University of Cambridge)

  • Richard Butler

    (University of Cambridge)

  • Gillian Clifford

    (University of Edinburgh)

  • Marcus D. Wilson

    (University of Edinburgh)

  • Stephen P. Jackson

    (University of Cambridge
    University of Cambridge)

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.

Suggested Citation

  • Rimma Belotserkovskaya & Elisenda Raga Gil & Nicola Lawrence & Richard Butler & Gillian Clifford & Marcus D. Wilson & Stephen P. Jackson, 2020. "PALB2 chromatin recruitment restores homologous recombination in BRCA1-deficient cells depleted of 53BP1," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14563-y
    DOI: 10.1038/s41467-020-14563-y
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