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:
  • 金额:
    $ 32.88万
  • 依托单位:
  • 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

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

项目成果

期刊论文数量(0)
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Aimin Peng其他文献

Aimin Peng的其他文献

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{{ truncateString('Aimin Peng', 18)}}的其他基金

Greatwall in replication stress/DNA damage responses and oral cancer resistance
长城在复制应激/DNA损伤反应和口腔癌抵抗中的作用
  • 批准号:
    10991546
  • 财政年份:
    2024
  • 资助金额:
    $ 32.88万
  • 项目类别:
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:
    10738331
  • 财政年份:
    2021
  • 资助金额:
    $ 32.88万
  • 项目类别:
Greatwall in replication stress/DNA damage responses and oral cancer resistance
长城在复制应激/DNA损伤反应和口腔癌抵抗中的作用
  • 批准号:
    10175963
  • 财政年份:
    2021
  • 资助金额:
    $ 32.88万
  • 项目类别:
Greatwall in replication stress/DNA damage responses and oral cancer resistance
长城在复制应激/DNA损伤反应和口腔癌抵抗中的作用
  • 批准号:
    10545740
  • 财政年份:
    2021
  • 资助金额:
    $ 32.88万
  • 项目类别:
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
  • 财政年份:
    2021
  • 资助金额:
    $ 32.88万
  • 项目类别:
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:
    10312794
  • 财政年份:
    2021
  • 资助金额:
    $ 32.88万
  • 项目类别:
Greatwall in replication stress/DNA damage responses and oral cancer resistance
长城在复制应激/DNA损伤反应和口腔癌抵抗中的作用
  • 批准号:
    10383756
  • 财政年份:
    2021
  • 资助金额:
    $ 32.88万
  • 项目类别:
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:
    10381156
  • 财政年份:
    2021
  • 资助金额:
    $ 32.88万
  • 项目类别:
DNA Damage Checkpoint Recovery and Cancer
DNA 损伤检查点恢复与癌症
  • 批准号:
    8528303
  • 财政年份:
    2013
  • 资助金额:
    $ 32.88万
  • 项目类别:
DNA Damage Checkpoint Recovery and Cancer
DNA 损伤检查点恢复与癌症
  • 批准号:
    8634078
  • 财政年份:
    2013
  • 资助金额:
    $ 32.88万
  • 项目类别:

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