EPIGENETIC CONTROL OF NHEJ DNA REPAIR

NHEJ DNA 修复的表观遗传控制

基本信息

  • 批准号:
    8634733
  • 负责人:
  • 金额:
    $ 29.43万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-01-01 至 2016-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Transposase activity was thought to be extinct in humans because DNA movement can be deleterious in higher organisms, resulting in genomic instability and perhaps malignancy. However, we isolated a human transposase protein termed Metnase that had both a Transposase domain that functions as an endonuclease and a SET histone methylase domain. The Transposase domain has preferential endonuclease activity for supercoiled DNA, and the SET domain was able to methylate histone 3 at lysine 36, associated with open chromatin. Metnase enhances resistance to radiation therapy, and improves repair of DNA double strand breaks (DSBs) via the non-homologous end-joining pathway (NHEJ). Both the SET and Transposase domains were required for the NHEJ repair activity. Metnase was found to interact with the NBS1, an early NHEJ repair pathway component, DNA Ligase IV, a final component of the NHEJ pathway, and Pso4, an uncharacterized DSB repair component. We found that Metnase decreases the incidence of long deletions at the repaired DSB junction site. Metnase is phosphorylated at S495, and this is essential for its NHEJ repair activity. We show that Metnase decreases the rate of inter-chromosomal translocation when there are simultaneous DSBs on distinct chromosomes, consistent with its NHEJ repair activity. We also found that Metnase also mediates resistance to Topo II poisons, which cause DSBs, in cancer cell lines. Thus, Metnase is a novel component of the NHEJ repair pathway, and links histone modification to DSB repair. The mechanism by which Metnase improves DNA repair is unknown, but its SET histone methylase domain is essential to its NHEJ activity. Recent studies in yeast indicate that the modification of chromatin, including histone methylation, may be an important part of DSB repair. However, despite its potential importance, the connection between such epigenetic chromatin modifications and NHEJ DSB repair is not well defined. Using a novel ChIP assay to analyze proteins associated with a single defined DSB, we found that Metnase localized to that DSB, and dimethylated H3K36 there. We also found evidence that dimethylated H3K36 may recruit early NHEJ components, such as ATM and the MRN complex, to the DSB. Based on these data, we hypothesize that Metnase plays an important role in the epigenetic regulation of NHEJ DSB repair. This hypothesis will be explored in four aims that translate molecular mechanisms to clinical relevance- 1) What are the structures of Metnase that are essential for its histone methylase activity? 2) What are the histone alterations Metnase makes around a DSB sites? 3) What is the mechanism by which Metnase's histone methylation enhances DSB repair? 4) Can the histone methylase activity of Metnase be exploited clinically?
描述(由申请人提供): 转座酶活性被认为在人类中已经灭绝,因为DNA移动在高等生物中可能是有害的,导致基因组不稳定性和可能的恶性肿瘤。然而,我们分离出一种称为Metnase的人转座酶蛋白,其具有作为内切核酸酶的转座酶结构域和SET组蛋白甲基化酶结构域。转座酶结构域对超螺旋DNA具有优先的核酸内切酶活性,并且SET结构域能够在与开放染色质相关的赖氨酸36处甲基化组蛋白3。Metnase增强对放射疗法的抗性,并通过非同源末端连接途径(NHEJ)改善DNA双链断裂(DSB)的修复。SET和转座酶结构域都是NHEJ修复活性所需的。 发现Metnase与NBS 1(早期NHEJ修复途径组分)、DNA连接酶IV(NHEJ途径的最终组分)和Pso 4(未表征的DSB修复组分)相互作用。我们发现Metnase降低了修复的DSB连接位点长缺失的发生率。Metnase在S495处磷酸化,这对其NHEJ修复活性至关重要。我们表明,当不同染色体上同时存在DSB时,Metnase降低了染色体间易位的速率,这与其NHEJ修复活性一致。我们还发现,Metnase还介导对Topo II毒物的抗性,这会导致癌细胞系中的DSB。因此,Metnase是NHEJ修复途径的新组分,并将组蛋白修饰与DSB修复联系起来。 Metnase改善DNA修复的机制尚不清楚,但其SET组蛋白甲基化酶结构域对其NHEJ活性至关重要。最近的研究表明,染色质的修饰,包括组蛋白甲基化,可能是DSB修复的重要组成部分。然而,尽管其潜在的重要性,这种表观遗传染色质修饰和NHEJ DSB修复之间的联系还没有很好地定义。使用一种新的ChIP测定来分析与单个定义的DSB相关的蛋白质,我们发现Metnase定位于该DSB,并且在那里二甲基化H3 K36。我们还发现证据表明,二甲基化H3 K36可能会招募早期NHEJ组件,如ATM和MRN复合物,DSB。基于这些数据,我们假设Metnase在NHEJ DSB修复的表观遗传调控中起重要作用。这一假设将在四个目标中进行探索,这些目标将分子机制转化为临床相关性- 1)Metnase的结构对其组蛋白甲基化酶活性至关重要?2)Metnase在DSB位点周围的组蛋白改变是什么?3)Metnase的组蛋白甲基化增强DSB修复的机制是什么?4)Metnase的组蛋白甲基化酶活性能否用于临床?

项目成果

期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Overview for the histone codes for DNA repair.
Adenomatous polyposis coli-mediated accumulation of abasic DNA lesions lead to cigarette smoke condensate-induced neoplastic transformation of normal breast epithelial cells.
腺瘤性息肉病大肠杆菌介导的无碱基 DNA 损伤的积累导致香烟烟雾冷凝物诱导正常乳腺上皮细胞的肿瘤性转化。
  • DOI:
    10.1593/neo.13176
  • 发表时间:
    2013
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Jaiswal,ArunaS;Panda,Harekrushna;Pampo,ChristineA;Siemann,DietmarW;Gairola,CGary;Hromas,Robert;Narayan,Satya
  • 通讯作者:
    Narayan,Satya
Cellular Responses to Widespread DNA Replication Stress.
Repressing DNA repair to enhance chemotherapy: targeting MyD88 in colon cancer.
{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Robert A Hromas其他文献

Robert A Hromas的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Robert A Hromas', 18)}}的其他基金

EEPD1 Repair of Stressed Replication Forks
EEPD1 修复压力复制叉
  • 批准号:
    10585067
  • 财政年份:
    2016
  • 资助金额:
    $ 29.43万
  • 项目类别:
EEPD1 Repair of Stressed Replication Forks
EEPD1 修复压力复制叉
  • 批准号:
    9082924
  • 财政年份:
    2016
  • 资助金额:
    $ 29.43万
  • 项目类别:
Mechanisms for Chromosomal Translocations
染色体易位的机制
  • 批准号:
    9187481
  • 财政年份:
    2015
  • 资助金额:
    $ 29.43万
  • 项目类别:
Mechanisms for Chromosomal Translocations
染色体易位的机制
  • 批准号:
    9029327
  • 财政年份:
    2015
  • 资助金额:
    $ 29.43万
  • 项目类别:
EPIGENETIC CONTROL OF NHEJ DNA REPAIR
NHEJ DNA 修复的表观遗传控制
  • 批准号:
    8007448
  • 财政年份:
    2010
  • 资助金额:
    $ 29.43万
  • 项目类别:
EPIGENETIC CONTROL OF NHEJ DNA REPAIR
NHEJ DNA 修复的表观遗传控制
  • 批准号:
    8402671
  • 财政年份:
    2010
  • 资助金额:
    $ 29.43万
  • 项目类别:
EPIGENETIC CONTROL OF NHEJ DNA REPAIR
NHEJ DNA 修复的表观遗传控制
  • 批准号:
    8204607
  • 财政年份:
    2010
  • 资助金额:
    $ 29.43万
  • 项目类别:
EPIGENETIC CONTROL OF NHEJ DNA REPAIR
NHEJ DNA 修复的表观遗传控制
  • 批准号:
    8453406
  • 财政年份:
    2010
  • 资助金额:
    $ 29.43万
  • 项目类别:
EPIGENETIC CONTROL OF NHEJ DNA REPAIR
NHEJ DNA 修复的表观遗传控制
  • 批准号:
    7784624
  • 财政年份:
    2010
  • 资助金额:
    $ 29.43万
  • 项目类别:
TRANSPOSASES IN ETOPOSIDE RESISTANCE
依托泊苷抗性中的转座酶
  • 批准号:
    8192937
  • 财政年份:
    2009
  • 资助金额:
    $ 29.43万
  • 项目类别:

相似海外基金

How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
  • 批准号:
    BB/Z514391/1
  • 财政年份:
    2024
  • 资助金额:
    $ 29.43万
  • 项目类别:
    Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
  • 批准号:
    2312555
  • 财政年份:
    2024
  • 资助金额:
    $ 29.43万
  • 项目类别:
    Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
  • 批准号:
    2327346
  • 财政年份:
    2024
  • 资助金额:
    $ 29.43万
  • 项目类别:
    Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
  • 批准号:
    ES/Z502595/1
  • 财政年份:
    2024
  • 资助金额:
    $ 29.43万
  • 项目类别:
    Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
  • 批准号:
    23K24936
  • 财政年份:
    2024
  • 资助金额:
    $ 29.43万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
  • 批准号:
    ES/Z000149/1
  • 财政年份:
    2024
  • 资助金额:
    $ 29.43万
  • 项目类别:
    Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
  • 批准号:
    2901648
  • 财政年份:
    2024
  • 资助金额:
    $ 29.43万
  • 项目类别:
    Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
  • 批准号:
    488039
  • 财政年份:
    2023
  • 资助金额:
    $ 29.43万
  • 项目类别:
    Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
  • 批准号:
    23K00129
  • 财政年份:
    2023
  • 资助金额:
    $ 29.43万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
  • 批准号:
    2883985
  • 财政年份:
    2023
  • 资助金额:
    $ 29.43万
  • 项目类别:
    Studentship
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了