Defining the role of BARD1 in nucleosomal ubiquitylation
Defining the role of BARD1 in nucleosomal ubiquitylation
批准号:
10368107
负责人:
PETER S BRZOVIC
金额:
$52.72万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-04-01 至 2026-03-31
关键词:
AddressAnkyrin RepeatArchitectureBARD1 geneBRCA1 ProteinBRCA1 geneBRCT DomainBehaviorBindingBiochemicalBiologicalBiophysicsBreast Cancer PatientCell physiologyCellsChemicalsClinicalComplexCryoelectron MicroscopyDNADNA RepairDetectionDeuteriumDiseaseEMSAGenesGoalsHereditary Malignant NeoplasmHistone H2AHistonesHydrogenKnowledgeLearningLengthLigaseMalignant neoplasm of ovaryModificationMolecularMolecular ConformationMutationNucleosomesPatientsPhenotypePoly Adenosine Diphosphate RibosePositioning AttributePredispositionProteinsReportingResectedResolutionRoleSiteStructureTailTestingTranscriptional RegulationTumor Suppressor ProteinsUbiquitinWorkbiophysical techniquescancer predispositioncrosslinkdesigngene repressionhomologous recombinationinsightloss of functionmalignant breast neoplasmmutantrecruitshared attentionubiquitin-protein ligase
中文摘要
项目摘要
BARD 1(BRCA 1相关环结构域蛋白-1)是乳腺的重要伴侣,
卵巢癌肿瘤抑制蛋白BRCA 1,包括在一组基因中,
评估疑似遗传性癌症易感性的患者,尤其是乳腺癌和卵巢癌
癌的尽管如此,人们对BARD 1的细胞作用知之甚少。该项目旨在
通过在分子水平上定义BARD 1如何发挥作用,
DNA损伤修复和转录抑制。最终目标是使
预测患者中鉴定的突变的潜在功能丧失表型。
BRCA 1和其专性伴侣BARD 1形成异二聚体复合物,其涉及
许多细胞过程,最值得注意的是,转录调节和DNA修复,
同源重组唯一的酶活性直接与
BRCA 1/BARD 1复合物是E3泛素连接酶。BRCA 1和BRCA 2的RING结构域
BARD 1特异性和独特地靶向核小体组蛋白H2 A尾部的位置。的
BRCA 1/BARD 1放置这些Ub标记的能力对于其转录和表达都是至关重要的。
抑制某些基因及其在DNA损伤修复中的功能
重组虽然BRCA 1的RING是所有连接酶活性所必需的,但乳腺癌患者
BARD 1的RING中的突变显示出H2 A的泛素化特异性功能丧失。一
新确定的BRCA 1/BARD 1 RING结构域的冷冻电镜结构位于一个
核小体揭示BARD 1决定E3连接酶的方向,因此,
确定H2 A上的修饰位点。在这个项目中,我们将建立在这个令人兴奋的新的
结构洞察力,以解决BARD 1的RING以外的区域如何有助于其作为一个
BRCA 1的重要伙伴。
英文摘要
PROJECT SUMMARY
BARD1 (BRCA1-Associated RING Domain protein-1) is an essential partner of the breast and
ovarian cancer tumor-suppressor protein, BRCA1, and is included in a panel of genes used to
evaluate patients with suspected hereditary cancer predisposition, especially breast and ovarian
cancers. Despite this, little is known about the cellular role of BARD1. This project aims to
address this serious gap in knowledge by defining at a molecular level how BARD1 contributes
to DNA damage repair and to transcriptional repression. An ultimate goal is to enable
predictions regarding potential loss-of-function phenotypes for mutations identified in patients.
BRCA1 and its obligate partner BARD1 form a heterodimeric complex that is implicated in
numerous cellular processes, most notably, transcriptional regulation and DNA repair via
homologous recombination. The sole enzymatic activity directly associated with the
BRCA1/BARD1 complex is as an E3 Ubiquitin ligase. The RING domains of BRCA1 and
BARD1 specifically and uniquely target positions on the tail of nucleosomal histone H2A. The
ability of BRCA1/BARD1 to place these Ub marks is essential to both its transcriptional
repression of certain genes and its function in DNA damage repair by homologous
recombination. While the RING of BRCA1 is required for all ligase activity, breast cancer patient
mutations in the RING of BARD1 display loss-of-function specifically for ubiquitylation of H2A. A
newly determined cryo-EM structure of the BRCA1/BARD1 RING domains sitting atop a
nucleosome reveals that BARD1 dictates the orientation of the E3 ligase and, therefore,
determines the site(s) of modification on H2A. In this project, we will build on this exciting new
structural insight to address how regions outside BARD1’s RING contribute to its function as an
essential partner of BRCA1.
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Defining the role of BARD1 in nucleosomal ubiquitylation
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批准号:10610818
-
项目类别:
-
资助金额:$52.72万
-
财政年份:2021
-
负责人:PETER S BRZOVIC
-
依托单位:
Defining the role of BARD1 in nucleosomal ubiquitylation
-
批准号:10231875
-
项目类别:
-
资助金额:$61.91万
-
财政年份:2021
-
负责人:PETER S BRZOVIC
-
依托单位:
Unconventional Interactions of Human Ubiquitin Conjugating Enzymes
-
批准号:8528627
-
项目类别:
-
资助金额:$27.29万
-
财政年份:2012
-
负责人:PETER S BRZOVIC
-
依托单位:
Unconventional Interactions of Human Ubiquitin Conjugating Enzymes
-
批准号:8716782
-
项目类别:
-
资助金额:$28.25万
-
财政年份:2012
-
负责人:PETER S BRZOVIC
-
依托单位:
Unconventional Interactions of Human Ubiquitin Conjugating Enzymes
-
批准号:8293759
-
项目类别:
-
资助金额:$28.32万
-
财政年份:2012
-
负责人:PETER S BRZOVIC
-
依托单位:
Unconventional Interactions of Human Ubiquitin Conjugating Enzymes
-
批准号:9276349
-
项目类别:
-
资助金额:$4.87万
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财政年份:2012
-
负责人:PETER S BRZOVIC
-
依托单位:
海外基金