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

描述（由申请人提供）：MRN-ATM通路主要参与DNA双链断裂（DSB）的感知、信号传导和修复。DSB是由于外部损伤（如电离辐射）而产生的，并且在DNA复制期间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途径如何调节对DSB的DNA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与DNA的相互作用，以及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，我们将确定如何MRN和ATM合作，以维持基因组的稳定性，在DSB的存在。我们的系统来分析这些问题仍然是非洲爪蟾卵细胞无提取物。MRN-ATM通路是对DSB应答的中心节点，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（A-T）、共济失调毛细血管扩张样障碍（ATLD）、奈梅亨断裂综合征（NBS）、范可尼贫血（FA）、BRCA 1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如何通过MRN-ATM途径维持基因组稳定性，防止肿瘤发生。此外，由于MRN-ATM途径是治疗干预的靶点，因此更好地理解MRN-ATM途径如何发挥作用的机制有助于鉴定具有辐射保护或辐射增敏潜力的化合物。 公共卫生相关性：MRN/CtIP-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）、奈梅亨断裂综合征（NBS）、范可尼贫血（FA）或BRCA 1相关的乳腺癌和卵巢癌易感性。CtIP是本竞争性修订申请中提出的研究重点，也已显示在小鼠模型中作为肿瘤抑制因子。我们预计，我们的研究将有助于解释如何通过MRN/CtIP-ATM途径维持基因组稳定性，防止肿瘤发生。此外，由于 MRN/CtIP-ATM通路是治疗干预的靶点，更好地了解MRN/CtIP-ATM通路的作用机制有助于设计更好的治疗方案。

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.