- EMDB-23592: Cryo-EM structure of the human nucleosome core particle ubiquityl... -
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Basic information
Entry
Database: EMDB / ID: EMD-23592
Title
Cryo-EM structure of the human nucleosome core particle ubiquitylated at histone H2A Lys13 and Lys15 in complex with BARD1 (residues 415-777)
Map data
Sample
Complex: Human nucleosome core particle ubiquitylated at histone H2A Lys13 and Lys15 in complex with BARD1 (residues 415-777)
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: Ubiquitin
Protein or peptide: BRCA1-associated RING domain protein 1
Protein or peptide: Histone H2A type 1-B/E
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 / nuclear ubiquitin ligase complex / DNA strand resection involved in replication fork processing / homologous recombination ...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 / nuclear ubiquitin ligase complex / DNA strand resection involved in replication fork processing / homologous recombination / tissue homeostasis / protein K6-linked ubiquitination / regulation of DNA damage checkpoint / regulation of phosphorylation / Impaired BRCA2 binding to PALB2 / mitotic G2/M transition checkpoint / negative regulation of protein export from nucleus / hypothalamus gonadotrophin-releasing hormone neuron development / 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 / female meiosis I / Homologous DNA Pairing and Strand Exchange / Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA) / positive regulation of protein monoubiquitination / mitochondrion transport along microtubule / Resolution of D-loop Structures through Holliday Junction Intermediates / fat pad development / HDR through Single Strand Annealing (SSA) / Impaired BRCA2 binding to RAD51 / female gonad development / seminiferous tubule development / male meiosis I / positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator / Presynaptic phase of homologous DNA pairing and strand exchange / negative regulation of cell cycle / heterochromatin organization / negative regulation of tumor necrosis factor-mediated signaling pathway / negative regulation of megakaryocyte differentiation / nucleosomal DNA binding / protein localization to CENP-A containing chromatin / Chromatin modifying enzymes / regulation of DNA repair / Replacement of protamines by nucleosomes in the male pronucleus / CENP-A containing nucleosome / epigenetic regulation of gene expression / energy homeostasis / regulation of neuron apoptotic process / Packaging Of Telomere Ends / regulation of proteasomal protein catabolic process / ubiquitin ligase complex / Recognition and association of DNA glycosylase with site containing an affected purine / Cleavage of the damaged purine / Maturation of protein E / Maturation of protein E / Deposition of new CENPA-containing nucleosomes at the centromere / ER Quality Control Compartment (ERQC) / Myoclonic epilepsy of Lafora / FLT3 signaling by CBL mutants / Prevention of phagosomal-lysosomal fusion / IRAK2 mediated activation of TAK1 complex / Alpha-protein kinase 1 signaling pathway / Glycogen synthesis / IRAK1 recruits IKK complex / IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation / Membrane binding and targetting of GAG proteins / Recognition and association of DNA glycosylase with site containing an affected pyrimidine / Cleavage of the damaged pyrimidine / Endosomal Sorting Complex Required For Transport (ESCRT) / IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / Negative regulation of FLT3 / Constitutive Signaling by NOTCH1 HD Domain Mutants / Regulation of FZD by ubiquitination / TICAM1,TRAF6-dependent induction of TAK1 complex / NOTCH2 Activation and Transmission of Signal to the Nucleus / TICAM1-dependent activation of IRF3/IRF7 / APC/C:Cdc20 mediated degradation of Cyclin B / Inhibition of DNA recombination at telomere / Meiotic synapsis / p75NTR recruits signalling complexes / Downregulation of ERBB4 signaling / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / APC-Cdc20 mediated degradation of Nek2A / PINK1-PRKN Mediated Mitophagy / telomere organization / TRAF6-mediated induction of TAK1 complex within TLR4 complex / Pexophagy / Regulation of innate immune responses to cytosolic DNA / VLDLR internalisation and degradation / InlA-mediated entry of Listeria monocytogenes into host cells / Downregulation of ERBB2:ERBB3 signaling / RNA Polymerase I Promoter Opening / NF-kB is activated and signals survival / Interleukin-7 signaling / NRIF signals cell death from the nucleus / Regulation of PTEN localization / Activated NOTCH1 Transmits Signal to the Nucleus / Regulation of BACH1 activity / Assembly of the ORC complex at the origin of replication Similarity search - Function
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
Jun 16, 2021
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Map release
Jun 16, 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
PDB-7lyc: Cryo-EM structure of the human nucleosome core particle ubiquitylated at histone H2A Lys13 and Lys15 in complex with BARD1 (residues 415-777)
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