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

描述（由申请人提供）：MRN-ATM途径主要参与DNA双链断裂（dsb）的传感、信号传导和修复。dsb的产生是外部损伤的结果，如电离辐射，并在DNA复制过程中在所有循环细胞中产生。如果不修复，它们可能导致突变和染色体重排、易位或丢失。本提案的长期目标是了解MRN-ATM途径如何调节DNA对dsb的损伤反应。具体来说，我们将研究ATM和MRN如何与DNA相互作用，ATM如何调节MRN-DNA相互作用，反过来，MRN如何影响ATM对DNA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如何在dsb存在的情况下合作维持基因组稳定性。我们分析这些问题的系统仍然是爪蟾卵细胞无提取物。MRN-ATM通路是对dsb反应的中心节点，该通路或其下游靶点的缺陷与遗传性癌症易感性综合征相关，包括共济失调毛细血管扩张症（a- t）、共济失调毛细血管扩张样疾病（ATLD）、奈梅根断裂综合征（NBS）、范可尼贫血（FA）、brca1相关的乳腺癌和卵巢癌易感性。我们预计我们的研究将有助于解释MRN-ATM途径如何维持基因组稳定性以防止肿瘤发生。此外，由于MRN-ATM途径是治疗干预的靶点，因此更好地了解MRN-ATM途径的功能机制有助于识别具有放射保护或放射致敏潜力的化合物。

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. PUBLIC HEALTH RELEVANCE: The MRN/CtIP-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), Nijmegen Breakage Syndrome (NBS), Fanconi Anemia (FA) or BRCA1-associated breast and ovarian cancer susceptibility. CtIP, the focus of the studies proposed in this competitive revision application has also been shown to act as a tumor suppressor in a mouse model. We anticipate that our studies will help explain how maintenance of genome stability by the MRN/CtIP-ATM pathway protects from tumorigenesis. Furthermore, since the MRN/CtIP-ATM pathway is a target for therapeutic intervention, a better mechanistic understanding of how the MRN/CtIP-ATM pathway functions could help design better therapies.