Structural biology of DNA damage response in chromatin
染色质 DNA 损伤反应的结构生物学
基本信息
- 批准号:10569017
- 负责人:
- 金额:$ 39.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-05-01 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:BRCA1 geneBiochemistryBreast Cancer CellCancer PatientCellular biologyChromatinCryoelectron MicroscopyDNA DamageDNA Double Strand BreakDNA RepairDNA Repair GeneDouble Strand Break RepairEquilibriumGoalsHealthHistone H2AHistonesHumanKnowledgeLysineMaintenanceMalignant neoplasm of ovaryMolecularMolecular ChaperonesNMR SpectroscopyNonhomologous DNA End JoiningNucleosome Core ParticleNucleosomesPathway interactionsPhosphorylationPlayPoly(ADP-ribose) Polymerase InhibitorPost-Translational Protein ProcessingProteinsPublic HealthResearchResistanceRing Finger DomainRoleSiteTestingTumor SuppressionUbiquitin-Conjugating EnzymesVariantWorkX-Ray Crystallographyataxia telangiectasia mutated proteinfascinategenome integrityhomologous recombinationp53-binding protein 1programsrecombinational repairrecruitresponsestructural biologyubiquitin-protein ligase
项目摘要
Histone protein H2A and variant H2A.X play central roles in the cellular response to DNA double-strand breaks
(DSBs) in mammalian chromatin. Near DSBs, chromatin becomes enriched in H2A.X which gets
phosphorylated by ATM kinase. Phosphorylation of H2A.X sets off a cascade of post-translational
modifications (PTMs) culminating with the recruitment of RING-finger E3 ubiquitin ligase RNF168 to DNA
damage sites. RNF168 and cognate E2 ubiquitin-conjugating enzyme UbcH5c catalyze the mono-
ubiquitylation of histones H2A and H2A.X at lysine residues 13 and 15 (H2AK13ub and H2AK15ub) in the
nucleosome core particle. These two PTMs are recognized by and determine the recruitment to damaged
chromatin of several DNA damage response (DDR) proteins including 53BP1, BRCA1/RAP80, RAD18 and
RNF169 that control the balance between the DSB repair pathways of non-homologous end joining (NHEJ)
and homologous recombination (HR). The goal of this research program is to determine the molecular
mechanisms by which H2A and H2A.X are involved in the DDR. Using NMR spectroscopy, X-ray
crystallography, cryo-electron microscopy, biochemistry and cell biology, we will probe how RNF168-UbcH5c
generates H2AK13ub and H2AK15ub and how these PTMs are recognized by HR-promoting DDR proteins in
the context of the nucleosome. We will also test the hypothesis that ubiquitylation of H2A.X at lysine residues
13 or 15 directly contributes to chromatin decompaction, thereby facilitating the recruitment of DNA repair
proteins to DSBs. Finally, we will address the mechanism of H2A/H2A.X exchange and H2A.X enrichment at
DSBs promoted by human histone chaperone FACT. Collectively, our work will provide fundamental
knowledge relevant to NHEJ and HR repair mechanisms with important implications for human health as
explained in the Narrative paragraph. As is often the case in research, it is likely that new unanticipated and
fascinating questions will arise during our studies that, in keeping with the MIRA R35 mechanism, we will
tackle as needed.
组蛋白H_2A和变异型H_2A_X在细胞对DNA双链断裂的反应中起核心作用
(DSB)在哺乳动物染色质中。在DSB附近,染色质在H_2A.X中变得丰富,后者得到
被ATM激酶磷酸化。H_2A.X的磷酸化引发了一连串的翻译后
修饰(PTM),最终导致环指E3泛素连接酶RNF168与DNA的连接
损毁地点。RNF168和同源的E2泛素结合酶UbcH5c催化单链-
组蛋白H_2A和H_2A_X在赖氨酸残基13和15(H_2AK13ub和H_2AK15ub)上的泛素化
核小体核心颗粒。这两个PTM是被认可的,并决定招募到受损的
几种DNA损伤反应(DDR)蛋白包括53BP1、BRCA1/RAP80、RAD18和
控制非同源末端连接DSB修复通路之间平衡的RNF169(NHEJ)
和同源重组(HR)。这项研究计划的目标是确定分子
H_2A和H_2A.X参与DDR的机制。使用核磁共振波谱、X射线
结晶学、低温电子显微镜、生物化学和细胞生物学,我们将探索RNF168-UbcH5c
产生H2AK13ub和H2AK15ub,以及这些PTM是如何被HR促进的DDR蛋白识别的
核小体的背景。我们还将检验假设,赖氨酸残基上的H_2A.X泛素化
13或15直接促进染色质分解,从而促进DNA修复的招募
蛋白质转化为DSB。最后,我们将讨论H_2A/H_2A.X交换和H_2A.X浓缩的机制。
由人类组蛋白伴侣事实启动的双链断裂。总体而言,我们的工作将为
与NHEJ和HR修复机制相关的知识,对人类健康具有重要影响
在叙述性段落中进行了解释。就像研究中经常出现的情况一样,新的出乎意料的和
在我们的研究中将出现一些有趣的问题,根据Mira R35机制,我们将
根据需要进行处理。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Georges Mer', 18)}}的其他基金
Structural biology of DNA damage response in chromatin
染色质 DNA 损伤反应的结构生物学
- 批准号:
10360611 - 财政年份:2020
- 资助金额:
$ 39.75万 - 项目类别:
Structural basis of RNF168-mediated ubiquitin signaling at chromosomal DNA breaks
染色体 DNA 断裂时 RNF168 介导的泛素信号传导的结构基础
- 批准号:
9147614 - 财政年份:2015
- 资助金额:
$ 39.75万 - 项目类别:
Post-translational Modifications in DNA Damage Response: a Structural Perspective
DNA 损伤反应的翻译后修饰:结构视角
- 批准号:
8627747 - 财政年份:2013
- 资助金额:
$ 39.75万 - 项目类别:
Post-translational Modifications in DNA Damage Response: a Structural Perspective
DNA 损伤反应的翻译后修饰:结构视角
- 批准号:
9178635 - 财政年份:2013
- 资助金额:
$ 39.75万 - 项目类别:
Post-translational Modifications in DNA Damage Response: a Structural Perspective
DNA 损伤反应的翻译后修饰:结构视角
- 批准号:
8969666 - 财政年份:2013
- 资助金额:
$ 39.75万 - 项目类别:
Post-translational Modifications in DNA Damage Response: a Structural Perspective
DNA 损伤反应的翻译后修饰:结构视角
- 批准号:
8788387 - 财政年份:2013
- 资助金额:
$ 39.75万 - 项目类别:
Structural Biology of Lysine Methylation in DNA Damage and Checkpoint Signaling
DNA 损伤和检查点信号转导中赖氨酸甲基化的结构生物学
- 批准号:
8016109 - 财政年份:2008
- 资助金额:
$ 39.75万 - 项目类别:
Structural Biology of Lysine Methylation in DNA Damage and Checkpoint Signaling
DNA 损伤和检查点信号转导中赖氨酸甲基化的结构生物学
- 批准号:
8212403 - 财政年份:2008
- 资助金额:
$ 39.75万 - 项目类别:
Structural Biology of Lysine Methylation in DNA Damage and Checkpoint Signaling
DNA 损伤和检查点信号转导中赖氨酸甲基化的结构生物学
- 批准号:
7586836 - 财政年份:2008
- 资助金额:
$ 39.75万 - 项目类别:
Structural Biology of Lysine Methylation in DNA Damage and Checkpoint Signaling
DNA 损伤和检查点信号转导中赖氨酸甲基化的结构生物学
- 批准号:
7759525 - 财政年份:2008
- 资助金额:
$ 39.75万 - 项目类别:
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