Regulation of the DNA damage response by the MRN-ATM pathway

MRN-ATM 通路对 DNA 损伤反应的调节

基本信息

批准号：
8081784
负责人：
JEAN GAUTIER
金额：
$ 27.69万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-04-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8081784
关键词：
ATM Signaling Pathway ATM activation ATP phosphohydrolase Abbreviations Address Affect Arginine Ataxia Telangiectasia BRCA1 gene Behavior Biochemical Process Biological Assay Bypass C-terminal Cell Cycle Cells Complex DNA DNA Binding DNA Damage DNA Double Strand Break DNA Sequence Rearrangement DNA biosynthesis DNA replication fork Defect Disease Exhibits Exonuclease Fanconi&apos s Anemia Fluorescence Microscopy Genome Stability Individual Inherited Ionizing radiation Lead Maintenance Malignant Neoplasms Malignant neoplasm of ovary Modeling Modification Monitor NBS1 gene Nijmegen Breakage Syndrome Pathway interactions Pattern Point Mutation Post-Translational Protein Processing Predisposition Property Proteins Radio Reading Recombinants Recruitment Activity Regulation Role Signal Transduction Site Syndrome System Therapeutic Intervention Time Xenopus adenylate kinase ataxia telangiectasia mutated protein chromatin immunoprecipitation chromosome mutation egg endonuclease functional hypothalamic amenorrhea malignant breast neoplasm mutant plasmid DNA prevent protein complex reconstitution repaired replication factor A response single molecule tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The MRN-ATM pathway is primarily involved in sensing, signaling, and repairing DNA double-strand breaks (DSBs). DSBs arise as a consequence of external insults, such as ionizing radiation and are generated in all cycling cells during DNA replication. If unrepaired, they may lead to mutations and chromosome rearrangements, translocations or loss. The long-term objective of this proposal is to understand how the MRN-ATM pathway regulates DNA damage response to DSBs. Specifically, we will study how ATM and MRN interact with DNA, how ATM modulates MRN-DNA interactions and conversely how MRN affects ATM's behavior on DNA. Next, we will investigate the role of damaged DNA in ATM activation. Finally, we will determine how MRN and ATM cooperate to maintain genome stability in the presence of DSBs. Our system to analyze these questions remains Xenopus egg cell free extracts. The MRN-ATM pathway is a central node in the response to DSBs and defects in this pathway or its downstream targets are associated with inherited cancer susceptibility syndromes including Ataxia-Telangiectasia (A-T), Ataxia Telangiectasia like disorder (ATLD), Nijmegen Breakage Syndrome (NBS), Fanconi Anemia (FA), BRCA1-associated breast and ovarian cancer susceptibility. We anticipate that our studies will help explain how maintenance of genome stability by the MRN-ATM pathway protects from tumorigenesis. Furthermore, since the MRN-ATM pathway is a target for therapeutic intervention, a better mechanistic understanding of how the MRN-ATM pathway functions could help to identity compounds with radio-protective or radio-sensitizing potential.

描述（由申请人提供）：MRN-ATM途径主要涉及传感，信号和修复DNA双链断裂（DSB）。 DSB是由于外部侮辱而产生的，例如电离辐射，并在DNA复制过程中在所有循环细胞中产生。如果未修复，它们可能会导致突变和染色体重排，易位或损失。该提案的长期目标是了解MRN-ATM途径如何调节DNA损伤对DSB的响应。具体而言，我们将研究ATM和MRN与DNA相互作用，ATM如何调节MRN-DNA相互作用，并相反，MRN如何影响ATM在DNA上的行为。接下来，我们将研究受损DNA在ATM激活中的作用。最后，我们将确定MRN和ATM在存在DSB的情况下如何合作以保持基因组稳定性。我们分析这些问题的系统仍然是无爪蟾卵细胞提取物。 The MRN-ATM pathway is a central node in the response to DSBs and defects in this pathway or its downstream targets are associated with inherited cancer susceptibility syndromes including Ataxia-Telangiectasia (A-T), Ataxia Telangiectasia like disorder (ATLD), Nijmegen Breakage Syndrome (NBS), Fanconi Anemia (FA), BRCA1-associated breast and卵巢癌的敏感性。我们预计我们的研究将有助于解释MRN-ATM途径对基因组稳定性的维持如何保护肿瘤发生。此外，由于MRN-ATM途径是治疗干预的靶标，因此对MRN-ATM途径功能如何有助于具有无线电保护或无线电敏感电位的身份化合物有更好的机械理解。