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):

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.
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Robert A Hromas其他文献

Robert A Hromas的其他文献

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{{ 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:

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