Kinesin-8调控微管动态及减数分裂I期同源染色体分离的分子机制

微管动态调控对细胞极性建立、细胞分裂等基本细胞生命活动至关重要。Kinesin-8家族驱动蛋白是微管动态的关键调控蛋白，其能在微管上长时间持续性行走并具有抑制微管动态的功能。目前Kinesin-8的具体作用机制和微管调控功能仍存争议，急待进一步深入探讨。我们的近期研究表明微管动态调控需包括Kinesin-8和Mal3等多种微管结合蛋白协同并揭示Kinesin-8在减数分裂I期同源染色体分离时起关键调控作用。为此，本项目以裂殖酵母和人类细胞系为互补模式研究体系，结合利用包括TIRF显微镜观察等多种先进技术手段，聚焦研究Kinesin-8的微管动态调控机制及其调控减数分裂I期纺锤体动态和同源染色体分离的具体作用机理。Kinesin-8功能异常与多种癌症的发生发展紧密相关。因此，该项研究的成功实施将不仅推动人们系统理解Kinesin-8的微管调控功能，而且将为发展肿瘤干预策略奠定基础。

Microtubules are dynamic structures required for many fundamental activities, including the establishment of cell polarity and cell division, within the cell. Kinesin-8 plays a critical role in regulating microtubule dynamics and is known to possess high processivity on microtubules and to dampen microtubule dynamicity at microtubule plus ends. However, the mechanisms underlying microtubule dynamics by Kinesin-8 as proposed in the literature is controversial, and hence how kinesin-8 functions to regulate microtubule dynamics has remained elusive. In our previous work, we demonstrated that Kinesin-8 synergizes with the microtubule-plus-tip proteins Mal3/Tip1/Tea2 to restrict microtubule depolymerization to the cell end. In our preliminary study, we revealed that the absence of kinesin-8/klp5 leads to defective spindle dynamics and homologous chromosome segregation. Based on these findings, we aim to dissect the roles of kinesin-8 in regulating microtubule dynamics during interphase and spindle and chromosome dynamics during meiosis I, using a combination of spinning-disk and TIRF microscopy, biochemistry, and molecular and cell biological approaches. Malfunction of kinesin-8 is highly relevant to tumorigenesis. Hence, this work will not only provide important insights into the regulation of microtubule dynamics but also promote the development of new strategies for cancer intervention.