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-Structure paper
タイトル | BRCA1-BARD1 combines multiple chromatin recognition modules to bridge nascent nucleosomes. |
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ジャーナル・号・ページ | Nucleic Acids Res, Vol. 51, Issue 20, Page 11080-11103, Year 2023 |
掲載日 | 2023年11月10日 |
著者 | Hayden Burdett / Martina Foglizzo / Laura J Musgrove / Dhananjay Kumar / Gillian Clifford / Lisa J Campbell / George R Heath / Elton Zeqiraj / Marcus D Wilson / |
PubMed 要旨 | Chromatin association of the BRCA1-BARD1 heterodimer is critical to promote homologous recombination repair of DNA double-strand breaks (DSBs) in S/G2. How the BRCA1-BARD1 complex interacts with ...Chromatin association of the BRCA1-BARD1 heterodimer is critical to promote homologous recombination repair of DNA double-strand breaks (DSBs) in S/G2. How the BRCA1-BARD1 complex interacts with chromatin that contains both damage induced histone H2A ubiquitin and inhibitory H4K20 methylation is not fully understood. We characterised BRCA1-BARD1 binding and enzymatic activity to an array of mono- and di-nucleosome substrates using biochemical, structural and single molecule imaging approaches. We found that the BRCA1-BARD1 complex preferentially interacts and modifies di-nucleosomes over mono-nucleosomes, allowing integration of H2A Lys-15 ubiquitylation signals with other chromatin modifications and features. Using high speed- atomic force microscopy (HS-AFM) to monitor how the BRCA1-BARD1 complex recognises chromatin in real time, we saw a highly dynamic complex that bridges two nucleosomes and associates with the DNA linker region. Bridging is aided by multivalent cross-nucleosome interactions that enhance BRCA1-BARD1 E3 ubiquitin ligase catalytic activity. Multivalent interactions across nucleosomes explain how BRCA1-BARD1 can recognise chromatin that retains partial di-methylation at H4 Lys-20 (H4K20me2), a parental histone mark that blocks BRCA1-BARD1 interaction with nucleosomes, to promote its enzymatic and DNA repair activities. |
リンク | Nucleic Acids Res / PubMed:37823591 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 3.4 - 21.5 Å |
構造データ | EMDB-16859, PDB-8off: EMDB-16869: Low-resolution structure of BRCA1dExon11-FL BARD1 (closed state) EMDB-16870: Low-resolution structure of BRCA1dExon11-FL BARD1 (open state) EMDB-17928: Structure of BARD1 ARD-BRCTs in complex with H2AKc15ub nucleosomes (Map 2) |
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キーワード | DNA BINDING PROTEIN / BRCA1-BARD1 / chromatin recognition / nucleosomes / ubiquitin |