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-Structure paper
タイトル | Mechanisms of BRCA1-BARD1 nucleosome recognition and ubiquitylation. |
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ジャーナル・号・ページ | Nature, Vol. 596, Issue 7872, Page 438-443, Year 2021 |
掲載日 | 2021年7月28日 |
著者 | Qi Hu / Maria Victoria Botuyan / Debiao Zhao / Gaofeng Cui / Elie Mer / Georges Mer / |
PubMed 要旨 | The BRCA1-BARD1 tumour suppressor is an E3 ubiquitin ligase necessary for the repair of DNA double-strand breaks by homologous recombination. The BRCA1-BARD1 complex localizes to damaged chromatin ...The BRCA1-BARD1 tumour suppressor is an E3 ubiquitin ligase necessary for the repair of DNA double-strand breaks by homologous recombination. The BRCA1-BARD1 complex localizes to damaged chromatin after DNA replication and catalyses the ubiquitylation of histone H2A and other cellular targets. 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 breaks. We further show that RING domains 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 chromatin. These data provide a structural framework to evaluate BARD1 variants and help to identify mutations that drive the development of cancer. |
リンク | Nature / PubMed:34321665 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 2.91 - 3.28 Å |
構造データ | EMDB-23590, PDB-7lya: EMDB-23591, PDB-7lyb: EMDB-23592, PDB-7lyc: |
化合物 | ChemComp-ZN: |
由来 |
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キーワード | STRUCTURAL PROTEIN/DNA / Nucleosome core particle / chromatin / DNA replication / DNA repair / STRUCTURAL PROTEIN-DNA complex / BRCA1 / BARD1 / UbcH5c / DNA double-strand break / Homologous recombination / 53BP1 / ARD domain / Ankyrine repeat domain / Tandem BRCT domain / ubiquitin |