7LYC

Cryo-EM structure of the human nucleosome core particle ubiquitylated at histone H2A Lys13 and Lys15 in complex with BARD1 (residues 415-777)

7LYC の概要

• エントリーDOI: 10.2210/pdb7lyc/pdb
• EMDBエントリー: 23590 23591 23592
• 分子名称: Histone H3.1, Histone H4, Histone H2B type 1-J, ... (8 entities in total)
• 機能のキーワード: nucleosome core particle, chromatin, brca1, bard1, dna repair, dna double-strand break, homologous recombination, 53bp1, ard domain, ankyrine repeat domain, tandem brct domain, ubiquitin, structural protein-dna complex, structural protein/dna
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 251070.87

構造登録者

Hu, Q.,Botuyan, M.V.,Zhao, D.,Cui, D.,Mer, E.,Mer, G. (登録日: 2021-03-06, 公開日: 2021-06-16, 最終更新日: 2024-10-09)

主引用文献

Hu, Q.,Botuyan, M.V.,Zhao, D.,Cui, G.,Mer, E.,Mer, G.
Mechanisms of BRCA1-BARD1 nucleosome recognition and ubiquitylation.
Nature, 596:438-443, 2021

PubMed Abstract: 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.

PubMed: 34321665
DOI: 10.1038/s41586-021-03716-8

実験手法

ELECTRON MICROSCOPY (2.94 Å)