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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的基因组不稳定通常对细胞生长有害。矛盾的是，在癌症中，它与增加耐药、转移和免疫逃避；所有这些都会导致患者预后不良。更广泛的我们研究的目标是充分了解 DNA 损伤反应 (DDR) 途径和有丝分裂如何机器协同工作以促进忠实的基因组稳定性。 DDR 途径的一个主要组成部分是共济失调毛细血管扩张和 Rad3 相关 (ATR) 激酶。我之前发现了一种意想不到的、新颖的DNA损伤—— ATR 激酶在有丝分裂进入后的独立作用。新发现的 ATR 作用对于基因组至关重要稳定。 ATR 的这种意想不到的作用为理解 ATR 之间的串扰提供了许多机会。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规范作用来做出独特的贡献 DDR 通路的组成确保了基因组的稳定性。我们的五年目标是加深我们对 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 有丝分裂功能的理解仅限于我们之前观察到的 ATR 激活促进适当的 Aurora B 活性。这对于 ATR 如何促进适当的治疗留下了很大的知识空白。染色体分离。我们将探索 ATR 调节的有丝分裂途径，重点关注假定的直接我们已确定的底物（程序 1）。此外，我们之前的工作揭示了 ATR 的两个新颖的、独立于 DDR 的功能，我们的目标是充分利用它们在此提案中进行探索（方案 2）。 (1) ATR 在间期直接磷酸化核纤层蛋白 A/C。这就提示了我们来定义 ATR 对核可塑性和核膜破裂的功能。 (2) 基础 ATR 活性为对于整个间期的正确着丝粒身份是必需的。我们将重点关注基础 ATR 活性如何通过调节早幼粒细胞核体促进适当的着丝粒特性和功能。我们期望这些项目将产生关于 ATR 在有丝分裂中的作用以及它如何与 DNA 相互作用的重要信息。损伤反应途径促进独立于 DNA 损伤的忠实染色体分离，并进一步我们对促进基因组稳定性的机制的理解。