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RNF168-mediated localization of BARD1 recruits the BRCA1-PALB2 complex to DNA damage

Author

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  • John J. Krais

    (Molecular Therapeutics Program, Fox Chase Cancer Center)

  • Yifan Wang

    (Molecular Therapeutics Program, Fox Chase Cancer Center)

  • Pooja Patel

    (Molecular Therapeutics Program, Fox Chase Cancer Center)

  • Jayati Basu

    (Blood Cell Development and Function Program, Fox Chase Cancer Center)

  • Andrea J. Bernhardy

    (Molecular Therapeutics Program, Fox Chase Cancer Center)

  • Neil Johnson

    (Molecular Therapeutics Program, Fox Chase Cancer Center)

Abstract

DNA damage prompts a diverse range of alterations to the chromatin landscape. The RNF168 E3 ubiquitin ligase catalyzes the mono-ubiquitination of histone H2A at lysine (K)13/15 (mUb-H2A), forming a binding module for DNA repair proteins. BRCA1 promotes homologous recombination (HR), in part, through its interaction with PALB2, and the formation of a larger BRCA1-PALB2-BRCA2-RAD51 (BRCA1-P) complex. The mechanism by which BRCA1-P is recruited to chromatin surrounding DNA breaks is unclear. In this study, we reveal that an RNF168-governed signaling pathway is responsible for localizing the BRCA1-P complex to DNA damage. Using mice harboring a Brca1CC (coiled coil) mutation that blocks the Brca1-Palb2 interaction, we uncovered an epistatic relationship between Rnf168− and Brca1CC alleles, which disrupted development, and reduced the efficiency of Palb2-Rad51 localization. Mechanistically, we show that RNF168-generated mUb-H2A recruits BARD1 through a BRCT domain ubiquitin-dependent recruitment motif (BUDR). Subsequently, BARD1-BRCA1 accumulate PALB2-RAD51 at DNA breaks via the CC domain-mediated BRCA1-PALB2 interaction. Together, these findings establish a series of molecular interactions that connect the DNA damage signaling and HR repair machinery.

Suggested Citation

  • John J. Krais & Yifan Wang & Pooja Patel & Jayati Basu & Andrea J. Bernhardy & Neil Johnson, 2021. "RNF168-mediated localization of BARD1 recruits the BRCA1-PALB2 complex to DNA damage," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25346-4
    DOI: 10.1038/s41467-021-25346-4
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    Cited by:

    1. John J. Krais & David J. Glass & Ilse Chudoba & Yifan Wang & Wanjuan Feng & Dennis Simpson & Pooja Patel & Zemin Liu & Ryan Neumann-Domer & Robert G. Betsch & Andrea J. Bernhardy & Alice M. Bradbury &, 2023. "Genetic separation of Brca1 functions reveal mutation-dependent Polθ vulnerabilities," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Chao Yang & Zhenzhen Ma & Keshan Wang & Xingxiao Dong & Meiyu Huang & Yaqiu Li & Xiagu Zhu & Ju Li & Zhihui Cheng & Changhao Bi & Xueli Zhang, 2023. "HMGN1 enhances CRISPR-directed dual-function A-to-G and C-to-G base editing," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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