- EMDB-23591: Cryo-EM structure of the human nucleosome core particle in comple... -
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Basic information
Entry
Database: EMDB / ID: EMD-23591
Title
Cryo-EM structure of the human nucleosome core particle in complex with BRCA1-BARD1-UbcH5c
Map data
Sample
Complex: Human nucleosome core particle in complex with BRCA1-BARD1-UbcH5cNucleosome
Protein or peptide: Histone H3.1Histone H3
Protein or peptide: Histone H4
Protein or peptide: Histone H2B type 1-J
DNA: DNA (147-MER)
DNA: DNA (146-MER)
Protein or peptide: Isoform 7 of Breast cancer type 1 susceptibility protein
Protein or peptide: Ubiquitin-conjugating enzyme E2 D3
Protein or peptide: BRCA1-associated RING domain protein 1
Protein or peptide: Histone H2A type 1-B/E
Ligand: ZINC ION
Function / homology
Function and homology information
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 / cellular response to indole-3-methanol / negative regulation of fatty acid biosynthetic process / (E3-independent) E2 ubiquitin-conjugating enzyme / lateral element / homologous recombination / tissue homeostasis / Signaling by BMP / protein K6-linked ubiquitination / regulation of DNA damage checkpoint / dosage compensation by inactivation of X chromosome / regulation of phosphorylation / protein K11-linked ubiquitination / Impaired BRCA2 binding to PALB2 / XY body / : / mitotic G2/M transition checkpoint / negative regulation of protein export from nucleus / negative regulation of gene expression via chromosomal CpG island methylation / 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 / HDR through Single Strand Annealing (SSA) / Impaired BRCA2 binding to RAD51 / DNA-binding transcription activator activity / E2 ubiquitin-conjugating enzyme / response to ionizing radiation / intracellular non-membrane-bounded organelle / Transcriptional Regulation by E2F6 / protein monoubiquitination / mitotic G2 DNA damage checkpoint signaling / ubiquitin conjugating enzyme activity / Presynaptic phase of homologous DNA pairing and strand exchange / negative regulation of BMP signaling pathway / negative regulation of cell cycle / heterochromatin organization / negative regulation of tumor necrosis factor-mediated signaling pathway / positive regulation of vascular endothelial growth factor production / negative regulation of reactive oxygen species metabolic process / negative regulation of megakaryocyte differentiation / nucleosomal DNA binding / localization / protein localization to CENP-A containing chromatin / protein autoubiquitination / protein K48-linked ubiquitination / Chromatin modifying enzymes / regulation of DNA repair / Replacement of protamines by nucleosomes in the male pronucleus / CENP-A containing nucleosome / 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 / ubiquitin ligase complex / 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 / Meiotic synapsis / positive regulation of DNA repair / 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 methylation / IKK complex recruitment mediated by RIP1 / Condensation of Prophase Chromosomes / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / SIRT1 negatively regulates rRNA expression / Chromatin modifications during the maternal to zygotic transition (MZT) / HCMV Late Events / innate immune response in mucosa / PRC2 methylates histones and DNA Similarity search - Function
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 / Ubiquitin-conjugating enzyme / 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 / Ring finger / Histone H2B signature. / Histone H2B / Histone H2B / Histone H2A conserved site / Histone H2A signature. / Histone H2A, C-terminal domain / C-terminus of histone H2A / Histone H2A / Histone 2A / Histone H4, conserved site / Histone H4 signature. / Histone H4 / Histone 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. / Ankyrin repeat / Histone H3 / Histone H3/CENP-A / 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 Similarity search - Domain/homology
Histone H2A type 1-B/E / Histone H2B type 1-J / Breast cancer type 1 susceptibility protein / Ubiquitin-conjugating enzyme E2 D3 / Histone H4 / Histone H3.1 / BRCA1-associated RING domain protein 1 Similarity search - Component
Biological species
Homo sapiens (human)
Method
single particle reconstruction / cryo EM / Resolution: 3.28 Å
National Institutes of Health/National Cancer Institute (NIH/NCI)
R01 CA132878
United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R35 GM136262
United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R01 GM116829
United States
Citation
Journal: Nature / Year: 2021 Title: Mechanisms of BRCA1-BARD1 nucleosome recognition and ubiquitylation. Authors: Qi Hu / Maria Victoria Botuyan / Debiao Zhao / Gaofeng Cui / Elie Mer / Georges Mer / 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 ...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.
History
Deposition
Mar 6, 2021
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Header (metadata) release
Jul 28, 2021
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Map release
Jul 28, 2021
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Update
Sep 1, 2021
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Current status
Sep 1, 2021
Processing site: RCSB / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
Macromolecule #6: Isoform 7 of Breast cancer type 1 susceptibility protein
Macromolecule
Name: Isoform 7 of Breast cancer type 1 susceptibility protein type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO / EC number: RING-type E3 ubiquitin transferase
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