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

• 批准号: 10524123
• 负责人: Aimin Peng
• 金额: $ 4.45万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10524123
• 关键词: ATM activation; ATP Hydrolysis; Acetylation; Autophagocytosis; Binding; Biochemical; Biology; Cancer Etiology; Cell Death; Cell Proliferation; Cell Survival; Cells; Chromatin; Chromatin Remodeling Factor; Chromatin Structure; Clinical; Communication; Complex; 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; Pharmacology; 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; protein complex; protein function; protein transport; recruit; repaired; response; segregation; therapy outcome; tool; tumor progression

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。作为对DNA损伤的反应，细胞激活了几个进化上保守的 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)，构成了重要的病因学 导致许多人类疾病的因素，尤其是癌症。此外，解除武装、复员和重返社会是 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用全面的方法描述新的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被迅速招募到DNA损伤站点 在DSB修复中起着至关重要的作用。值得注意的是，KIF2C调节DSB的空间运动，并且 控制DNA损伤引起的染色质重塑。KIF2C的这些功能在很大程度上依赖于 它的MT解聚酶活性，很可能通过与其他MT调节器的协调实现。在……上面 另一方面，DNA损伤调节KIF2C的磷酸化和MT的稳定。这些发现 在MT组件和DDR机制之间提出了一种不同的新的细胞器间串扰 与传统的认为MT仅作为细胞质结构发挥作用的看法不同。这些发现 也揭示了DNA损伤剂与抗MT的临床组合的新机制见解 癌症治疗中的毒药。在这个项目中，我们将进一步揭示KIF2C通过 调节DSB的流动性；我们将揭示KIF2C如何与染色质重整器和 其他MT监管机构将管理损害染色质的动态染色质压缩；我们将 ATM介导的KIF2C磷酸化及其对MT稳定性的调节 DNA损伤。总而言之，该项目可能会为DDR和DDR提供范式转换的补充 和MT生物学，并提高我们对细胞如何协调各种细胞成分的理解 以及在DNA损伤后维持基因组稳定和细胞动态平衡的机制。