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The novel role of microtubule regulators in the DNA damage response

微管调节剂在 DNA 损伤反应中的新作用

基本信息

批准号：
10549300
负责人：
Aimin Peng
金额：
$ 32.88万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10549300
关键词：
ATM activation ATP Hydrolysis Acetylation Autophagocytosis Binding Biochemical Biology Cancer Etiology Cell Death Induction Cell Proliferation Cell Survival Cells Chromatin Chromatin Remodeling Factor Chromatin Structure Clinical Communication Complex Cytoplasm Cytoplasmic Structures Cytoskeleton DNA DNA Damage DNA Double Strand Break DNA Repair Data Development Double Strand Break Repair Ensure Etiology Event Exhibits Family Genome Genome Stability Goals HDAC1 gene Homeostasis Human Hypersensitivity In Vitro Kinesin Kinetochores Knock-out Knowledge Laboratories Maintenance Therapy Malignant Neoplasms Mediating Microtubule Depolymerization Microtubule Stabilization Microtubules Mitotic Modeling Motor Movement Nonhomologous DNA End Joining Nuclear Organelles Perception Phosphorylation Physical condensation Play Poison Protein Array Proteins Radiation Regimen Regulation Relaxation Repairosome liposome Role Signal Transduction Site Therapeutic Toxic effect Tubulin Vesicle ataxia telangiectasia mutated protein cancer therapy chromatin remodeling condensin genome integrity histone methylation human disease improved in vivo innovation insight knock-down member mutant novel pharmacologic protein complex protein function protein transport recruit repaired response segregation therapy outcome tool tumor progression

项目摘要

DNA damage, particularly DNA double strand break (DSB), has detrimental effects on cell survival and genomic stability. In response to DNA damage, the cell activates several evolutionarily-conserved mechanisms to repair DNA damage, halt cell proliferation, or induce cell death. These surveillance mechanisms, collectively defined as the DNA damage response (DDR), constitute an important etiological factor for many human diseases, especially cancer. Moreover, the DDR is a key determinant for the therapeutic outcome of cancer treatment using radiation and other DNA damaging agents. A long-term goal of our laboratory is to delineate new DDR factors and mechanisms using comprehensive experimental tools, and thereby, revealing new insights into cancer progression and treatment. In a recent effort to systematically identify new components of the DSB “repairosome”, we identified Kif2C and several other MT regulators as potential DSB-associated proteins. Kif2C is rapidly recruited to DNA damage sites and plays an essential role in DSB repair. Strikingly, Kif2C mediates the spatial movement of DSBs, and controls DNA damage-induced chromatin remodeling. These functions of Kif2C are largely dependent on its MT depolymerase activity, and are likely to be achieved via coordination with other MT regulators. On the other hand, DNA damage modulates Kif2C phosphorylation and MT stabilization. These findings suggest a novel inter-organelle crosstalk between MT components and the DDR machinery that differs from the conventional perception that MT functions exclusively as a cytoplasmic structure. These findings also reveal new mechanistic insights into the clinical combinations of DNA damaging agents with anti-MT poisons in cancer therapy. In this project, we will further reveal detailed mechanisms via which Kif2C modulates the mobility of DSBs; we will uncover how Kif2C acts in concert with chromatin remodelers and other MT regulators to govern the dynamic chromatin compaction at damage chromatin; we will functionally characterize ATM-mediated Kif2C phosphorylation, and regulation of MT stabilization after DNA damage. Together, the project will potentially provide paradigm shifting additions to both the DDR and MT biology, and improve our understanding of how the cell coordinates various cellular components and mechanisms to maintain genomic stability and cell homeostasis after DNA damage.

DNA 损伤，特别是 DNA 双链断裂 (DSB)，对细胞存活和基因组稳定性。为了应对 DNA 损伤，细胞激活了一些进化上保守的基因修复 DNA 损伤、阻止细胞增殖或诱导细胞死亡的机制。这些监视机制，统称为DNA损伤反应（DDR），构成了一个重要的病因学许多人类疾病，尤其是癌症的因素。此外，DDR是一个关键的决定因素。使用辐射和其他 DNA 损伤剂治疗癌症的治疗结果。一个长期的我们实验室的目标是利用综合的方法来描述新的 DDR 因素和机制实验工具，从而揭示癌症进展和治疗的新见解。在最近的一次为了系统地鉴定 DSB“修复体”的新成分，我们鉴定了 Kif2C 和几个其他 MT 调节因子作为潜在的 DSB 相关蛋白。 Kif2C 被快速招募到 DNA 损伤位点并在 DSB 修复中发挥重要作用。引人注目的是，Kif2C 介导 DSB 的空间运动，并且控制 DNA 损伤诱导的染色质重塑。 Kif2C的这些功能很大程度上依赖于其 MT 解聚酶活性，并且可能通过与其他 MT 调节剂协调来实现。在另一方面，DNA 损伤调节 Kif2C 磷酸化和 MT 稳定性。这些发现提出了 MT 组件和 DDR 机器之间的一种新颖的细胞器间串扰，该串扰不同传统观念认为 MT 只作为细胞质结构发挥作用。这些发现还揭示了 DNA 损伤剂与抗 MT 临床组合的新机制见解癌症治疗中的毒物。在这个项目中，我们将进一步揭示 Kif2C 的详细机制调节 DSB 的移动性；我们将揭示 Kif2C 如何与染色质重塑剂协同作用，其他 MT 调节因子，用于控制染色质损伤处的动态染色质压缩；我们将功能表征 ATM 介导的 Kif2C 磷酸化，以及 MT 稳定后的调节 DNA损伤。总之，该项目将有可能为 DDR 和 DDR 提供范式转变的补充。和 MT 生物学，提高我们对细胞如何协调各种细胞成分的理解 DNA 损伤后维持基因组稳定性和细胞稳态的机制。