Elucidating how ATR promotes genome stability independent of the DNA damage response pathway

阐明 ATR 如何独立于 DNA 损伤反应途径促进基因组稳定性

• 批准号: 10711931
• 负责人: Lilian Carolina Kabeche
• 金额: $ 41.88万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711931
• 关键词: ATR gene; Centromere; Cessation of life; Chromosome Segregation; DNA Damage; Drug resistance; Ensure; Genome Stability; Genomic Instability; Goals; Immune Evasion; Interphase; Knowledge; Lamin Type A; Link; Malignant Neoplasms; Mitosis; Mitotic; Molecular; Neoplasm Metastasis; Nuclear; Nuclear Envelope; Pathway interactions; Phosphorylation; Phosphotransferases; Progranulocytes; Proteins; Regulation; Research; Role; Work; cancer cell; cell growth; novel; patient prognosis; programs; response; tumor progression

ABSTRACT Genome instability is generally deleterious to cell growth. Paradoxically, in cancer, it is associated with increased drug resistance, metastasis and immune evasion; all of which contribute to poor patient prognosis. The broader landscape of our research is to fully understand how the DNA damage response (DDR) pathway and mitotic machinery work in concert to promote faithful genome stability. A major component of the DDR pathway is Ataxia telangiectasia and Rad3 related (ATR) kinase. I previously discovered an unexpected, and novel DNA damage- independent, role for ATR kinase after mitotic entry. This newly revealed role for ATR is essential for genome stability. This unexpected role for ATR opened up many opportunities to understand cross-talk between the pathways that regulate genomic stability and is foundational to my lab. Our long-term goal is to make unique contributions by elucidating how the non-canonical roles of the proteins that make up the DDR pathway ensure genome stability. Our five-year goal is to further our understanding of the mechanisms by which ATR promotes genome stability outside of the DNA damage response pathway in both mitosis (program 1) and interphase (program 2). Our current understanding of the mitotic function of ATR is limited to our previous observations that ATR activates promotes proper Aurora B activity. This leaves a large gap of knowledge as to how ATR promotes proper chromosome segregation. We will explore the mitotic pathways that ATR regulates, focusing on putative direct substrates that we have identified (program 1). Additionally, our previous work uncovered two novel, DDR independent functions of ATR, which we aim to fully explore in this proposal (program 2). (1) ATR directly phosphorylates lamin A/C in interphase. This has prompted us to define the function of ATR on nuclear plasticity and nuclear envelope breakdown. (2) Basal ATR activity is necessary for proper centromere identity throughout interphase. We will focus on how basal ATR activity promotes proper centromere identity and function through its regulation of promyelocytic nuclear bodies. We expect that these projects will yield critical information on the role of ATR in mitosis and how it and the DNA damage response pathway promote faithful chromosome segregation independent of DNA damage and further our understanding of the mechanism that promote genome stability.

摘要 基因组不稳定性通常对细胞生长有害。奇怪的是，在癌症中， 耐药性、转移和免疫逃避;所有这些都导致患者预后不良。更广泛的 我们的研究前景是充分了解DNA损伤反应（DDR）途径和有丝分裂 机器协同工作以促进忠实的基因组稳定性。DDR途径的主要组成部分是共济失调 毛细血管扩张和Rad 3相关（ATR）激酶。我之前发现了一种意想不到的新的DNA损伤 独立，ATR激酶的作用后，有丝分裂进入。ATR的这一新发现的作用对于基因组 稳定ATR的这一意想不到的角色为理解 调节基因组稳定性的途径，是我实验室的基础。 我们的长期目标是通过阐明蛋白质的非经典作用如何 确保了基因组的稳定性。我们的五年目标是进一步了解 ATR在DNA损伤反应途径之外促进基因组稳定性的机制， 有丝分裂（程序1）和间期（程序2）。 我们目前对ATR的有丝分裂功能的理解仅限于我们以前的观察，即ATR激活 促进适当的极光B活性。这就留下了一个很大的知识空白，以ATR如何促进适当的 染色体分离我们将探讨ATR调控的有丝分裂途径，重点是推定的直接调控。 我们已经确定的底物（程序1）。 此外，我们以前的工作揭示了ATR的两个新颖的DDR独立功能，我们的目标是充分利用它们。 在这个项目中（项目2）。(1)ATR直接磷酸化间期核纤层蛋白A/C。这促使 明确ATR在核可塑性和核膜破裂中的作用。(2)基础ATR活性为 这是整个间期正确的着丝粒身份所必需的。我们将重点关注基础ATR活动 通过其对早幼粒细胞核体的调节促进适当的着丝粒身份和功能。 我们希望这些项目将产生ATR在有丝分裂中的作用以及它和DNA如何相互作用的关键信息。 损伤反应途径促进不依赖于DNA损伤的忠实染色体分离， 我们对促进基因组稳定性的机制的理解。