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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），对细胞的生存和发育具有不利的影响