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：
10738331
负责人：
Aimin Peng
金额：
$ 4.46万
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 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10738331
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，尤其是DNA双链断裂（DSB），对细胞存活和基因组稳定性。为了响应DNA损伤，该细胞激活了几个进化保存的修复DNA损伤，停止细胞增殖或诱导细胞死亡的机制。这些监视统称为DNA损伤响应（DDR）的机制构成了重要的病因许多人类疾病，尤其是癌症的因素。此外，DDR是使用辐射和其他DNA损伤剂对癌症治疗的治疗结果。长期我们实验室的目标是使用全面描述新的DDR因素和机制实验工具，从而揭示了对癌症进展和治疗的新见解。在最近的一个我们努力系统地识别DSB“ Reprionosome”的新组件，我们确定了KIF2C和几个其他MT调节剂作为潜在的DSB相关蛋白。 KIF2C迅速招募到DNA损伤位点并在DSB修复中起着至关重要的作用。令人惊讶的是，KIF2C介导了DSB的空间运动，控制DNA损伤诱导的染色质重塑。 KIF2C的这些功能在很大程度上取决于它的MT去聚合酶活性，很可能通过与其他MT调节剂的协调来实现。在另一方面，DNA损伤调节KIF2C磷酸化和MT稳定。这些发现建议在MT组件和DDR机械之间进行新颖的轨道间串扰从常规的看法中，MT仅作为细胞质结构起作用。这些发现还揭示了与抗MT的DNA破坏剂的临床组合的新机械见解癌症治疗中的毒药。在这个项目中，我们将进一步揭示通过KIF2C的详细机制调节DSB的移动性；我们将发现KIF2C如何与染色质远程共同行动和其他MT调节剂控制损伤染色质时动态染色质压实；我们将在功能上表征了ATM介导的KIF2C磷酸化，并调节MT稳定 DNA损伤。该项目共同为两个DDR提供了范式转换的添加和MT生物学，并提高我们对细胞如何坐标各种细胞成分的理解以及在DNA损伤后保持基因组稳定性和细胞稳态的机制。