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-C complex / BRCA1-B complex / BRCA1-A complex / negative regulation of centriole replication ...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-C complex / BRCA1-B complex / BRCA1-A complex / negative regulation of centriole replication / sex-chromosome dosage compensation / random inactivation of X chromosome / nuclear ubiquitin ligase complex / ubiquitin-modified histone reader activity / chordate embryonic development / negative regulation of intracellular estrogen receptor signaling pathway / cellular response to indole-3-methanol / gamma-tubulin ring complex / negative regulation of fatty acid biosynthetic process / DNA strand resection involved in replication fork processing / homologous recombination / Regulation of MITF-M-dependent genes involved in DNA replication, damage repair and senescence / tissue homeostasis / Signaling by BMP / regulation of phosphorylation / protein K6-linked ubiquitination / (E3-independent) E2 ubiquitin-conjugating enzyme / lateral element / regulation of DNA damage checkpoint / Impaired BRCA2 binding to PALB2 / XY body / mitotic G2/M transition checkpoint / negative regulation of protein export from nucleus / protein K11-linked ubiquitination / centrosome cycle / RNA polymerase binding / postreplication repair / DNA repair complex / positive regulation of protein targeting to mitochondrion / 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) / intracellular membraneless organelle / E2 ubiquitin-conjugating enzyme / response to ionizing radiation / negative regulation of gene expression via chromosomal CpG island methylation / Impaired BRCA2 binding to RAD51 / mitotic G2 DNA damage checkpoint signaling / Transcriptional Regulation by E2F6 / ubiquitin conjugating enzyme activity / negative regulation of cell cycle / negative regulation of reactive oxygen species metabolic process / Presynaptic phase of homologous DNA pairing and strand exchange / positive regulation of vascular endothelial growth factor production / negative regulation of BMP signaling pathway / protein monoubiquitination / ubiquitin ligase complex / SUMOylation of DNA damage response and repair proteins / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / protein K48-linked ubiquitination / negative regulation of megakaryocyte differentiation / regulation of DNA repair / protein localization to CENP-A containing chromatin / Chromatin modifying enzymes / protein autoubiquitination / Replacement of protamines by nucleosomes in the male pronucleus / CENP-A containing nucleosome / Packaging Of Telomere Ends / TICAM1, RIP1-mediated IKK complex recruitment / Recognition and association of DNA glycosylase with site containing an affected purine / Cleavage of the damaged purine / IKK complex recruitment mediated by RIP1 / PINK1-PRKN Mediated Mitophagy / 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 / telomere organization / cellular response to ionizing radiation / tubulin binding / Interleukin-7 signaling / Inhibition of DNA recombination at telomere / RNA Polymerase I Promoter Opening / Meiotic synapsis / Negative regulators of DDX58/IFIH1 signaling / Assembly of the ORC complex at the origin of replication / positive regulation of DNA repair / Regulation of endogenous retroelements by the Human Silencing Hub (HUSH) complex / SUMOylation of chromatin organization proteins / Peroxisomal protein import / DNA methylation / Condensation of Prophase Chromosomes / Downregulation of SMAD2/3:SMAD4 transcriptional activity / Chromatin modifications during the maternal to zygotic transition (MZT) / Regulation of TNFR1 signaling / SIRT1 negatively regulates rRNA expression / HCMV Late Events 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) / BRCA1 C Terminus (BRCT) domain / Ubiquitin-conjugating enzyme, active site ...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) / BRCA1 C Terminus (BRCT) domain / Ubiquitin-conjugating enzyme, active site / Ubiquitin-conjugating (UBC) active site signature. / Ubiquitin-conjugating enzyme E2 / Ubiquitin-conjugating enzyme / Ubiquitin-conjugating (UBC) core domain profile. / Ubiquitin-conjugating enzyme E2, catalytic domain homologues / Ubiquitin-conjugating enzyme/RWD-like / breast cancer carboxy-terminal domain / BRCT domain profile. / BRCT domain / BRCT domain superfamily / Zinc finger, RING-type, conserved site / Zinc finger RING-type signature. / Ring finger / : / 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 / Histone H4, conserved site / Histone H4 signature. / Histone H4 / Histone H4 / CENP-T/Histone H4, histone fold / Ankyrin repeats (3 copies) / Centromere kinetochore component CENP-T histone fold / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily / Zinc finger RING-type profile. / Zinc finger, RING-type / Histone H3 signature 1. / Histone H3 signature 2. / Histone H3 / Histone H3/CENP-A / 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
Truncated breast and ovarian cancer susceptibility protein 1 / Histone H2B type 1-K / Breast cancer type 1 susceptibility protein / Ubiquitin-conjugating enzyme E2 D3 / Histone H4 / Histone H2A type 2-A / Histone H3.2 / BRCA1-associated RING domain protein 1 類似検索 - 構成要素
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R01GM088055
米国
引用
ジャーナル: Nat Struct Mol Biol / 年: 2021 タイトル: BRCA1/BARD1 site-specific ubiquitylation of nucleosomal H2A is directed by BARD1. 著者: Samuel R Witus / Anika L Burrell / Daniel P Farrell / Jianming Kang / Meiling Wang / Jesse M Hansen / Alex Pravat / Lisa M Tuttle / Mikaela D Stewart / Peter S Brzovic / Champak Chatterjee / ...著者: Samuel R Witus / Anika L Burrell / Daniel P Farrell / Jianming Kang / Meiling Wang / Jesse M Hansen / Alex Pravat / Lisa M Tuttle / Mikaela D Stewart / Peter S Brzovic / Champak Chatterjee / Weixing Zhao / Frank DiMaio / Justin M Kollman / Rachel E Klevit / 要旨: Mutations in the E3 ubiquitin ligase RING domains of BRCA1/BARD1 predispose carriers to breast and ovarian cancers. We present the structure of the BRCA1/BARD1 RING heterodimer with the E2 enzyme ...Mutations in the E3 ubiquitin ligase RING domains of BRCA1/BARD1 predispose carriers to breast and ovarian cancers. We present the structure of the BRCA1/BARD1 RING heterodimer with the E2 enzyme UbcH5c bound to its cellular target, the nucleosome, along with biochemical data that explain how the complex selectively ubiquitylates lysines 125, 127 and 129 in the flexible C-terminal tail of H2A in a fully human system. The structure reveals that a novel BARD1-histone interface couples to a repositioning of UbcH5c compared to the structurally similar PRC1 E3 ligase Ring1b/Bmi1 that ubiquitylates H2A Lys119 in nucleosomes. This interface is sensitive to both H3 Lys79 methylation status and mutations found in individuals with cancer. Furthermore, NMR reveals an unexpected mode of E3-mediated substrate regulation through modulation of dynamics in the C-terminal tail of H2A. Our findings provide insight into how E3 ligases preferentially target nearby lysine residues in nucleosomes by a steric occlusion and distancing mechanism.