- EMDB-23591: Cryo-EM structure of the human nucleosome core particle in comple... -
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基本情報
登録情報
データベース: EMDB / ID: EMD-23591
タイトル
Cryo-EM structure of the human nucleosome core particle in complex with BRCA1-BARD1-UbcH5c
マップデータ
試料
複合体: Human nucleosome core particle in complex with BRCA1-BARD1-UbcH5cヌクレオソーム
タンパク質・ペプチド: Histone H3.1ヒストンH3
タンパク質・ペプチド: Histone H4ヒストンH4
タンパク質・ペプチド: Histone H2B type 1-J
DNA: DNA (147-MER)
DNA: DNA (146-MER)
タンパク質・ペプチド: Isoform 7 of Breast cancer type 1 susceptibility protein
タンパク質・ペプチド: Ubiquitin-conjugating enzyme E2 D3
タンパク質・ペプチド: BRCA1-associated RING domain protein 1
タンパク質・ペプチド: Histone H2A type 1-B/E
リガンド: ZINC ION
機能・相同性
機能・相同性情報
negative regulation of mRNA 3'-end processing / Defective DNA double strand break response due to BRCA1 loss of function / Defective DNA double strand break response due to BARD1 loss of function / : / BRCA1-BARD1 complex / BRCA1-C complex / BRCA1-B complex / BRCA1-A complex / random inactivation of X chromosome / negative regulation of centriole replication ...negative regulation of mRNA 3'-end processing / Defective DNA double strand break response due to BRCA1 loss of function / Defective DNA double strand break response due to BARD1 loss of function / : / BRCA1-BARD1 complex / BRCA1-C complex / BRCA1-B complex / BRCA1-A complex / random inactivation of X chromosome / negative regulation of centriole replication / negative regulation of intracellular estrogen receptor signaling pathway / gamma-tubulin ring complex / nuclear ubiquitin ligase complex / chordate embryonic development / DNA strand resection involved in replication fork processing / negative regulation of fatty acid biosynthetic process / (E3-independent) E2 ubiquitin-conjugating enzyme / cellular response to indole-3-methanol / 相同組換え / lateral element / tissue homeostasis / XY body / protein K6-linked ubiquitination / Signaling by BMP / regulation of DNA damage checkpoint / regulation of phosphorylation / dosage compensation by inactivation of X chromosome / negative regulation of gene expression via chromosomal CpG island methylation / protein K11-linked ubiquitination / Impaired BRCA2 binding to PALB2 / mitotic G2/M transition checkpoint / : / negative regulation of protein export from nucleus / postreplication repair / DNA repair complex / RNA polymerase binding / centrosome cycle / Defective homologous recombination repair (HRR) due to BRCA1 loss of function / Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function / Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function / Homologous DNA Pairing and Strand Exchange / Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA) / Resolution of D-loop Structures through Holliday Junction Intermediates / positive regulation of protein targeting to mitochondrion / ユビキチン結合酵素 / HDR through Single Strand Annealing (SSA) / Impaired BRCA2 binding to RAD51 / response to ionizing radiation / DNA-binding transcription activator activity / intracellular non-membrane-bounded organelle / Transcriptional Regulation by E2F6 / protein monoubiquitination / ubiquitin conjugating enzyme activity / mitotic G2 DNA damage checkpoint signaling / Presynaptic phase of homologous DNA pairing and strand exchange / negative regulation of BMP signaling pathway / negative regulation of cell cycle / positive regulation of vascular endothelial growth factor production / negative regulation of tumor necrosis factor-mediated signaling pathway / protein K48-linked ubiquitination / negative regulation of reactive oxygen species metabolic process / protein autoubiquitination / negative regulation of megakaryocyte differentiation / protein localization to CENP-A containing chromatin / localization / regulation of DNA repair / Chromatin modifying enzymes / Replacement of protamines by nucleosomes in the male pronucleus / CENP-A containing nucleosome / ubiquitin ligase complex / SUMOylation of DNA damage response and repair proteins / epigenetic regulation of gene expression / Packaging Of Telomere Ends / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / Recognition and association of DNA glycosylase with site containing an affected purine / Cleavage of the damaged purine / Deposition of new CENPA-containing nucleosomes at the centromere / Recognition and association of DNA glycosylase with site containing an affected pyrimidine / Cleavage of the damaged pyrimidine / Inhibition of DNA recombination at telomere / positive regulation of DNA repair / Meiotic synapsis / telomere organization / RNA Polymerase I Promoter Opening / Interleukin-7 signaling / Assembly of the ORC complex at the origin of replication / SUMOylation of chromatin organization proteins / tubulin binding / TICAM1, RIP1-mediated IKK complex recruitment / DNAメチル化 / IKK complex recruitment mediated by RIP1 / Condensation of Prophase Chromosomes / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / Chromatin modifications during the maternal to zygotic transition (MZT) / SIRT1 negatively regulates rRNA expression / HCMV Late Events / innate immune response in mucosa / PRC2 methylates histones and DNA / male germ cell nucleus / Defective pyroptosis 類似検索 - 分子機能
BARD1, Zinc finger, RING-type / zf-RING of BARD1-type protein / Breast cancer type 1 susceptibility protein (BRCA1) / BRCA1, serine-rich domain / BRCA1-associated / Serine-rich domain associated with BRCT / Zinc finger, C3HC4 RING-type / Zinc finger, C3HC4 type (RING finger) / Ubiquitin-conjugating enzyme, active site / Ubiquitin-conjugating (UBC) active site signature. ...BARD1, Zinc finger, RING-type / zf-RING of BARD1-type protein / Breast cancer type 1 susceptibility protein (BRCA1) / BRCA1, serine-rich domain / BRCA1-associated / Serine-rich domain associated with BRCT / Zinc finger, C3HC4 RING-type / Zinc finger, C3HC4 type (RING finger) / Ubiquitin-conjugating enzyme, active site / Ubiquitin-conjugating (UBC) active site signature. / BRCA1 C Terminus (BRCT) domain / Ubiquitin-conjugating enzyme E2, catalytic domain homologues / Ubiquitin-conjugating enzyme E2 / ユビキチン結合酵素 / Ubiquitin-conjugating (UBC) core domain profile. / Ubiquitin-conjugating enzyme/RWD-like / breast cancer carboxy-terminal domain / Zinc finger, RING-type, conserved site / Zinc finger RING-type signature. / BRCT domain profile. / BRCT domain / BRCT domain superfamily / 薬指 / Histone H2B signature. / ヒストンH2B / ヒストンH2B / Histone H2A conserved site / Histone H2A signature. / Histone H2A, C-terminal domain / C-terminus of histone H2A / ヒストンH2A / Histone 2A / Histone H4, conserved site / Histone H4 signature. / ヒストンH4 / ヒストンH4 / CENP-T/Histone H4, histone fold / Centromere kinetochore component CENP-T histone fold / TATA box binding protein associated factor / TATA box binding protein associated factor (TAF), histone-like fold domain / Ankyrin repeats (3 copies) / Histone H3 signature 1. / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ankyrin repeats / Histone H3 signature 2. / ヒストンH3 / Histone H3/CENP-A / Ankyrin repeat / Zinc finger RING-type profile. / Zinc finger, RING-type / Ankyrin repeat-containing domain superfamily / Histone H2A/H2B/H3 / Core histone H2A/H2B/H3/H4 / Histone-fold / Zinc finger, RING/FYVE/PHD-type 類似検索 - ドメイン・相同性
Histone H2A type 1-B/E / Histone H2B type 1-J / Breast cancer type 1 susceptibility protein / Ubiquitin-conjugating enzyme E2 D3 / ヒストンH4 / ヒストンH3 / BRCA1-associated RING domain protein 1 類似検索 - 構成要素
National Institutes of Health/National Cancer Institute (NIH/NCI)
R01 CA132878
米国
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R35 GM136262
米国
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R01 GM116829
米国
引用
ジャーナル: Nature / 年: 2021 タイトル: Mechanisms of BRCA1-BARD1 nucleosome recognition and ubiquitylation. 著者: Qi Hu / Maria Victoria Botuyan / Debiao Zhao / Gaofeng Cui / Elie Mer / Georges Mer / 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.