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- PDB-7e8i: Structural insight into BRCA1-BARD1 complex recruitment to damage... -

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Entry
Database: PDB / ID: 7e8i
TitleStructural insight into BRCA1-BARD1 complex recruitment to damaged chromatin
Components
  • (DNA (145-MER)) x 2
  • BRCA1-associated RING domain protein 1
  • Histone H2A
  • Histone H2B 1.1
  • Histone H3
  • Histone H4
  • Polyubiquitin-B
KeywordsNUCLEAR PROTEIN / BRCA1 / nucleosome / DNA damage / chromatin / BARD1
Function / homology
Function and homology information


negative regulation of mRNA 3'-end processing / histone H2AK127 ubiquitin ligase activity / histone H2AK129 ubiquitin ligase activity / 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-B complex / BRCA1-A complex / BRCA1-C complex / ubiquitin-modified histone reader activity ...negative regulation of mRNA 3'-end processing / histone H2AK127 ubiquitin ligase activity / histone H2AK129 ubiquitin ligase activity / 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-B complex / BRCA1-A complex / BRCA1-C complex / ubiquitin-modified histone reader activity / nuclear ubiquitin ligase complex / DNA strand resection involved in replication fork processing / homologous recombination / tissue homeostasis / protein K6-linked ubiquitination / regulation of phosphorylation / regulation of DNA damage checkpoint / Impaired BRCA2 binding to PALB2 / mitotic G2/M transition checkpoint / negative regulation of protein export from nucleus / Homologous DNA Pairing and Strand Exchange / 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 / Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA) / Resolution of D-loop Structures through Holliday Junction Intermediates / HDR through Single Strand Annealing (SSA) / Impaired BRCA2 binding to RAD51 / negative regulation of cell cycle / Presynaptic phase of homologous DNA pairing and strand exchange / ubiquitin ligase complex / regulation of DNA repair / cellular response to ionizing radiation / Nonhomologous End-Joining (NHEJ) / G2/M DNA damage checkpoint / RING-type E3 ubiquitin transferase / HDR through Homologous Recombination (HRR) / kinase binding / Metalloprotease DUBs / cytoplasmic ribonucleoprotein granule / ubiquitin-protein transferase activity / positive regulation of protein catabolic process / structural constituent of chromatin / UCH proteinases / nucleosome / heterochromatin formation / nucleosome assembly / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / Processing of DNA double-strand break ends / Regulation of TP53 Activity through Phosphorylation / regulation of cell cycle / nuclear speck / protein ubiquitination / positive regulation of apoptotic process / chromatin remodeling / protein heterodimerization activity / DNA repair / DNA damage response / regulation of transcription by RNA polymerase II / negative regulation of apoptotic process / protein homodimerization activity / DNA binding / RNA binding / zinc ion binding / nucleoplasm / nucleus / cytoplasm
Similarity search - Function
BARD1, Zinc finger, RING-type / zf-RING of BARD1-type protein / BRCT domain / Ankyrin repeat-containing domain / BRCA1 C Terminus (BRCT) domain / breast cancer carboxy-terminal domain / BRCT domain profile. / BRCT domain / BRCT domain superfamily / Zinc finger, RING-type, conserved site ...BARD1, Zinc finger, RING-type / zf-RING of BARD1-type protein / BRCT domain / Ankyrin repeat-containing domain / BRCA1 C Terminus (BRCT) domain / breast cancer carboxy-terminal domain / BRCT domain profile. / BRCT domain / BRCT domain superfamily / Zinc finger, RING-type, conserved site / Zinc finger RING-type signature. / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 1 / : / Histone H2B signature. / Histone H2A conserved site / Histone H2A signature. / Histone H2B / Histone H2B / Histone H2A, C-terminal domain / C-terminus of histone H2A / Histone 2A / Histone H2A / TATA box binding protein associated factor / TATA box binding protein associated factor (TAF), histone-like fold domain / Ankyrin repeats (3 copies) / Histone H4, conserved site / Histone H4 signature. / Histone H4 / Histone H4 / CENP-T/Histone H4, histone fold / Centromere kinetochore component CENP-T histone fold / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Zinc finger RING-type profile. / Ankyrin repeat-containing domain superfamily / Zinc finger, RING-type / Histone H3 signature 1. / Histone H3 signature 2. / Histone H3 / Histone H3/CENP-A / : / Ubiquitin domain signature. / Ubiquitin conserved site / Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat / Ubiquitin domain / Histone H2A/H2B/H3 / Core histone H2A/H2B/H3/H4 domain / Ubiquitin-like (UB roll) / Histone-fold / Ubiquitin family / Alpha Horseshoe / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Zinc finger, RING/FYVE/PHD-type / Ubiquitin-like domain superfamily / Roll / Rossmann fold / 3-Layer(aba) Sandwich / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
DNA / DNA (> 10) / DNA (> 100) / Histone H3 / Ubiquitin B / Histone H2B 1.1 / Histone H4 / Histone H2A / BRCA1-associated RING domain protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Xenopus laevis (African clawed frog)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsDai, Y. / Dai, L. / Zhou, Z.
Funding support China, 8items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)31671344 China
National Natural Science Foundation of China (NSFC)31871318 China
National Natural Science Foundation of China (NSFC)31970621 China
National Natural Science Foundation of China (NSFC)31801070 China
National Natural Science Foundation of China (NSFC)31730021 China
National Natural Science Foundation of China (NSFC)31971220 China
National Natural Science Foundation of China (NSFC)3170040161 China
National Natural Science Foundation of China (NSFC)31961160725 China
CitationJournal: Mol Cell / Year: 2021
Title: Structural insight into BRCA1-BARD1 complex recruitment to damaged chromatin.
Authors: Linchang Dai / Yaxin Dai / Jinhua Han / Yan Huang / Longge Wang / Jun Huang / Zheng Zhou /
Abstract: The BRCA1-BARD1 complex directs the DNA double-strand break (DSB) repair pathway choice to error-free homologous recombination (HR) during the S-G2 stages. Targeting BRCA1-BARD1 to DSB-proximal sites ...The BRCA1-BARD1 complex directs the DNA double-strand break (DSB) repair pathway choice to error-free homologous recombination (HR) during the S-G2 stages. Targeting BRCA1-BARD1 to DSB-proximal sites requires BARD1-mediated nucleosome interaction and histone mark recognition. Here, we report the cryo-EM structure of BARD1 bound to a ubiquitinated nucleosome core particle (NCP) at 3.1 Å resolution and illustrate how BARD1 simultaneously recognizes the DNA damage-induced mark H2AK15ub and DNA replication-associated mark H4K20me0 on the nucleosome. In vitro and in vivo analyses reveal that the BARD1-NCP complex is stabilized by BARD1-nucleosome interaction, BARD1-ubiquitin interaction, and BARD1 ARD domain-BARD1 BRCT domain interaction, and abrogating these interactions is detrimental to HR activity. We further identify multiple disease-causing BARD1 mutations that disrupt BARD1-NCP interactions and hence impair HR. Together, this study elucidates the mechanism of BRCA1-BARD1 complex recruitment and retention by DSB-flanking nucleosomes and sheds important light on cancer therapeutic avenues.
History
DepositionMar 1, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 30, 2021Provider: repository / Type: Initial release
Revision 1.0Jun 30, 2021Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jun 30, 2021Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jun 30, 2021Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Jun 30, 2021Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jun 30, 2021Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Jun 30, 2021Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jun 30, 2021Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Jul 14, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Mar 27, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Jul 2, 2025Group: Data collection / Structure summary / Category: em_admin / em_software / pdbx_entry_details / Item: _em_admin.last_update / _em_software.name
Revision 1.1Jul 2, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

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Assembly

Deposited unit
J: DNA (145-MER)
I: DNA (145-MER)
A: Histone H3
B: Histone H4
C: Histone H2A
D: Histone H2B 1.1
E: Histone H3
F: Histone H4
G: Histone H2A
H: Histone H2B 1.1
K: BRCA1-associated RING domain protein 1
L: Polyubiquitin-B


Theoretical massNumber of molelcules
Total (without water)247,50312
Polymers247,50312
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: native gel electrophoresis
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area61540 Å2
ΔGint-384 kcal/mol
Surface area89810 Å2

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Components

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DNA chain , 2 types, 2 molecules JI

#1: DNA chain DNA (145-MER)


Mass: 44992.648 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli K-12 (bacteria)
#2: DNA chain DNA (145-MER)


Mass: 44521.367 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli K-12 (bacteria)

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Protein , 6 types, 10 molecules AEBFCGDHKL

#3: Protein Histone H3


Mass: 15303.930 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog) / Gene: XELAEV_18002543mg / Production host: Escherichia coli K-12 (bacteria) / References: UniProt: A0A310TTQ1
#4: Protein Histone H4


Mass: 11263.231 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog) / Production host: Escherichia coli K-12 (bacteria) / References: UniProt: P62799
#5: Protein Histone H2A


Mass: 13952.205 Da / Num. of mol.: 2 / Mutation: K16C
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog)
Gene: h2ac14.L, h2ac14, hist1h2aj, LOC494591, XELAEV_18003602mg
Production host: Escherichia coli K-12 (bacteria) / References: UniProt: Q6AZJ8
#6: Protein Histone H2B 1.1 / H2B1.1


Mass: 13524.752 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog) / Production host: Escherichia coli K-12 (bacteria) / References: UniProt: P02281
#7: Protein BRCA1-associated RING domain protein 1 / BARD-1 / RING-type E3 ubiquitin transferase BARD1


Mass: 40145.836 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BARD1 / Production host: Escherichia coli K-12 (bacteria)
References: UniProt: Q99728, RING-type E3 ubiquitin transferase
#8: Protein Polyubiquitin-B


Mass: 9755.145 Da / Num. of mol.: 1 / Mutation: G76C
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: UBB / Production host: Escherichia coli K-12 (bacteria) / References: UniProt: J3QS39

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Details

Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1BARD1-NCP-Ubiquitin complexCOMPLEXall0MULTIPLE SOURCES
2DNACOMPLEX#1-#21RECOMBINANT
3HistoneCOMPLEX#3-#61RECOMBINANT
4BARD1-UbiquitinCOMPLEX#7-#81RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32Xenopus laevis (African clawed frog)8355
43Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
21Escherichia coli K-12 (bacteria)83333
32Escherichia coli K-12 (bacteria)83333
43Escherichia coli K-12 (bacteria)83333
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.17.1_3660: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 168313 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00516155
ELECTRON MICROSCOPYf_angle_d0.72723074
ELECTRON MICROSCOPYf_dihedral_angle_d26.6936533
ELECTRON MICROSCOPYf_chiral_restr0.0472622
ELECTRON MICROSCOPYf_plane_restr0.0041921

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