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Mechanisms of BRCA1–BARD1 nucleosome recognition and ubiquitylation

Author

Listed:
  • Qi Hu

    (Mayo Clinic)

  • Maria Victoria Botuyan

    (Mayo Clinic)

  • Debiao Zhao

    (Mayo Clinic)

  • Gaofeng Cui

    (Mayo Clinic)

  • Elie Mer

    (Mayo Clinic)

  • Georges Mer

    (Mayo Clinic
    Mayo Clinic)

Abstract

The BRCA1–BARD1 tumour suppressor is an E3 ubiquitin ligase necessary for the repair of DNA double-strand breaks by homologous recombination1–10. The BRCA1–BARD1 complex localizes to damaged chromatin after DNA replication and catalyses the ubiquitylation of histone H2A and other cellular targets11–14. The molecular bases for the recruitment to double-strand breaks and target recognition of BRCA1–BARD1 remain unknown. Here we use cryo-electron microscopy to show that the ankyrin repeat and tandem BRCT domains in BARD1 adopt a compact fold and bind to nucleosomal histones, DNA and monoubiquitin attached to H2A amino-terminal K13 or K15, two signals known to be specific for double-strand breaks15,16. We further show that RING domains17 in BRCA1–BARD1 orient an E2 ubiquitin-conjugating enzyme atop the nucleosome in a dynamic conformation, primed for ubiquitin transfer to the flexible carboxy-terminal tails of H2A and variant H2AX. Our work reveals a regulatory crosstalk in which recognition of monoubiquitin by BRCA1–BARD1 at the N terminus of H2A blocks the formation of polyubiquitin chains and cooperatively promotes ubiquitylation at the C terminus of H2A. These findings elucidate the mechanisms of BRCA1–BARD1 chromatin recruitment and ubiquitylation specificity, highlight key functions of BARD1 in both processes and explain how BRCA1–BARD1 promotes homologous recombination by opposing the DNA repair protein 53BP1 in post-replicative chromatin18–22. These data provide a structural framework to evaluate BARD1 variants and help to identify mutations that drive the development of cancer.

Suggested Citation

  • Qi Hu & Maria Victoria Botuyan & Debiao Zhao & Gaofeng Cui & Elie Mer & Georges Mer, 2021. "Mechanisms of BRCA1–BARD1 nucleosome recognition and ubiquitylation," Nature, Nature, vol. 596(7872), pages 438-443, August.
  • Handle: RePEc:nat:nature:v:596:y:2021:i:7872:d:10.1038_s41586-021-03716-8
    DOI: 10.1038/s41586-021-03716-8
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    Cited by:

    1. George E. Ronson & Katarzyna Starowicz & Elizabeth J. Anthony & Ann Liza Piberger & Lucy C. Clarke & Alexander J. Garvin & Andrew D. Beggs & Celina M. Whalley & Matthew J. Edmonds & James F. J. Beesle, 2023. "Mechanisms of synthetic lethality between BRCA1/2 and 53BP1 deficiencies and DNA polymerase theta targeting," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Gaofeng Cui & Maria Victoria Botuyan & Pascal Drané & Qi Hu & Benoît Bragantini & James R. Thompson & David J. Schuller & Alexandre Detappe & Michael T. Perfetti & Lindsey I. James & Stephen V. Frye &, 2023. "An autoinhibited state of 53BP1 revealed by small molecule antagonists and protein engineering," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    3. Jian Ma & Yingke Zhou & Penglin Pan & Haixin Yu & Zixi Wang & Lei Lily Li & Bing Wang & Yuqian Yan & Yunqian Pan & Qi Ye & Tianjie Liu & Xiaoyu Feng & Shan Xu & Ke Wang & Xinyang Wang & Yanlin Jian & , 2023. "TRABID overexpression enables synthetic lethality to PARP inhibitor via prolonging 53BP1 retention at double-strand breaks," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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