ENZYMOLOGY OF EUKARYOTIC DNA MISMATCH REPAIR

真核 DNA 错配修复的酶学

基本信息

  • 批准号:
    6138426
  • 负责人:
  • 金额:
    $ 31.14万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1991
  • 资助国家:
    美国
  • 起止时间:
    1991-01-01 至 2002-12-31
  • 项目状态:
    已结题

项目摘要

Human cells possess a strand-specific mismatch repair system that is a homolog of the bacterial and yeast pathways as judged by similarities in specificity, mechanism, and involvement of MutS and MutL-like activities. As in microbial systems, human mismatch repair mutations confer hypermutability. Genetic defects in the human repair system are the cause of hereditary nonpolyposis colon cancer, have been implicated in a subset of sporadic tumors that arise in a variety of tissues, and also confer resistance to certain chemotherapeutic agents, including DNA methylators and cisplatin. Clarification of the molecular nature of the human mismatch repair reaction is therefore relevant to both the origin and treatment of human malignancies. We and others have identified six activities that are involved in the human repair reaction: the mismatch recognition activities MutS-alpha (MSH2.MSH6 heterodimer) and MutS-beta (MSH2.MSH3 heterodimer), MutL-alpha (MLH1.PMS2 heterodimer), PCNA, RPA, and DNA polymerase delta. One of our major goals for the requested extension of this work will be the identification and isolation of other components of the repair system, with emphasis on helicase and/or exonuclease activities involved in the excision step of the reaction. This fractionation work will also include the isolation and characterization of several novel MutL-like activities that have been identified in extracts derived from HeLa cells and certain MLH1- deficient tumor and drug-resistant cell lines. The second aim of the work will be to further clarify the molecular roles of the required activities in the mismatch repair reaction. Initial studies will emphasize the assembly of the initiation complex, including protein- protein interactions, and the role of ATP in initiation complex formation and evolution. Should excision activities become available during the course of the project, the molecular studies will be extended to include these activities.
人类细胞具有链特异性错配修复系统,其是细菌和酵母途径的同源物,如通过MutS和MutL样活性的特异性、机制和参与的相似性来判断的。在微生物系统中,人类错配修复突变赋予超突变性。人类修复系统中的遗传缺陷是遗传性非息肉病性结肠癌的原因,与各种组织中出现的散发性肿瘤的子集有关,并且还赋予对某些化疗剂(包括DNA甲基化剂和顺铂)的抗性。因此,阐明人类错配修复反应的分子性质与人类恶性肿瘤的起源和治疗相关。我们和其他人已经确定了六种参与人类修复反应的活性:错配识别活性MutS-alpha(MSH2.MSH6异源二聚体)和MutS-beta(MSH2.MSH3异源二聚体),MutL-alpha(MLH1.PMS2异源二聚体),PCNA,RPA和DNA聚合酶δ。 我们的主要目标之一,要求延长这项工作将是修复系统的其他组件的识别和分离,强调在反应的切除步骤中涉及的解旋酶和/或核酸外切酶的活动。该分级分离工作还将包括几种新的MutL样活性的分离和表征,这些活性已在来自HeLa细胞和某些MLH 1缺陷型肿瘤和耐药细胞系的提取物中鉴定。这项工作的第二个目的是进一步阐明错配修复反应中所需活性的分子作用。初步研究将强调起始复合物的组装,包括蛋白质-蛋白质相互作用,以及ATP在起始复合物形成和进化中的作用。如果在项目执行过程中能够开展切除活动,将扩大分子研究,以包括这些活动。

项目成果

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PAUL LAWRENCE MODRICH其他文献

PAUL LAWRENCE MODRICH的其他文献

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{{ truncateString('PAUL LAWRENCE MODRICH', 18)}}的其他基金

Nucleic Acids 2008 Gordon Research Conference
核酸 2008 年戈登研究会议
  • 批准号:
    7477373
  • 财政年份:
    2008
  • 资助金额:
    $ 31.14万
  • 项目类别:
Mismatch Repair Interactions
错配修复相互作用
  • 批准号:
    7152387
  • 财政年份:
    2006
  • 资助金额:
    $ 31.14万
  • 项目类别:
Mismatch Repair Interactions
错配修复相互作用
  • 批准号:
    8555257
  • 财政年份:
    2001
  • 资助金额:
    $ 31.14万
  • 项目类别:
CORE--FERMENTATION FACILITY
核心--发酵设施
  • 批准号:
    6268738
  • 财政年份:
    1998
  • 资助金额:
    $ 31.14万
  • 项目类别:
CORE--FERMENTATION FACILITY
核心--发酵设施
  • 批准号:
    6236138
  • 财政年份:
    1997
  • 资助金额:
    $ 31.14万
  • 项目类别:
ENZYMOLOGY OF EUKARYOTIC DNA MISMATCH REPAIR
真核 DNA 错配修复的酶学
  • 批准号:
    2182980
  • 财政年份:
    1991
  • 资助金额:
    $ 31.14万
  • 项目类别:
ENZYMOLOGY OF EUKARYOTIC DNA MISMATCH REPAIR
真核 DNA 错配修复的酶学
  • 批准号:
    6342839
  • 财政年份:
    1991
  • 资助金额:
    $ 31.14万
  • 项目类别:
ENZYMOLOGY OF EUKARYOTIC DNA MISMATCH REPAIR
真核 DNA 错配修复的酶学
  • 批准号:
    3304558
  • 财政年份:
    1991
  • 资助金额:
    $ 31.14万
  • 项目类别:
Enzymology Of Eukaryotic Mismatch Repair
真核错配修复的酶学
  • 批准号:
    7336327
  • 财政年份:
    1991
  • 资助金额:
    $ 31.14万
  • 项目类别:
Enzymology and Eukaryotic Mismatch Repair
酶学和真核错配修复
  • 批准号:
    6837609
  • 财政年份:
    1991
  • 资助金额:
    $ 31.14万
  • 项目类别:
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