NEPhos_Phosphoregulation of ESCRT-III during nuclear envelope reformation

核膜是包裹真核细胞基因组的双层膜屏障，物理上将遗传物质与细胞质环境隔离开来。这就产生了一种选择性屏障，控制蛋白质在两个隔间之间的运输。在每个有丝分裂过程中，去甲肾上腺素在前期被分解，以便适当地分离复制的染色体，然后在后期/末期围绕两个新生的核重新组装。尽管激酶/磷酸酶启动和维持有丝分裂的回路已经被很好地定义，但后来的有丝分裂事件如何被微调以实现完整和及时的NE封闭仍然是不清楚的。我将使用遗传学、蛋白质组学、细胞生物学和成像方法的组合来阐明ESCRT-III机制是如何受到有丝分裂退出期间NE重塑部位的磷酸化/去磷酸化事件和蛋白质-蛋白质相互作用的调节的。了解指导核重组的机制将有助于更好地理解有丝分裂退出事件是如何在空间和时间上协调的，以确保在每个细胞周期中及时和有效的核质区隔。此外，NE缺陷是已知的疾病原因，因为染色质暴露在细胞质环境中对基因组稳定性构成威胁。由于ESCRT-III的解除调控可能导致NE完整性的损害，并最终导致核区划的丧失，对ESCRT-III蛋白在空间和时间上的作用的深入了解不仅可以揭示潜在的病理细胞机制的新见解，而且还可以揭示新的治疗方法。

The nuclear envelope (NE) is a double membrane barrier which encloses the genome of eukaryotic cells, physically shielding the genetic material from the cytoplasmic environment. This creates a selective barrier that regulates the trafficking of proteins between the two compartments. During each mitosis, the NE is dismantled in prophase to allow the proper segregation of the duplicated chromosomes and then reassembled around the two nascent nuclei in late anaphase/telophase. Even though the circuitry of kinases/ phosphatase initiating and sustaining mitosis is well defined, how the latter mitotic events are fine-tuned to achieve a complete and timely NE sealing are still ill-understood. I will use a combination of genetic, proteomic, cellular biology and imaging approaches to shed light on how the ESCRT-III machinery is regulated by phosphorylation/dephosphorylation events and protein-protein interactions at sites of NE reformation during mitotic exit. Understanding the mechanistical aspects guiding nuclear reassembly will allow a better understanding of how mitotic exit events are coordinated in space and time to ensure a timely and functional nucleocytoplasmic compartmentalisation at every cell cycle. Moreover, NE defects are a known cause of disease, as chromatin exposure to the cytoplasmic milieu poses a threat to genome stability. Since ESCRT-III deregulation can lead to an impairment of NE integrity and eventually to a loss of nuclear compartmentalisation, a deeper understanding of how ESCRT-III proteins act in space and time could reveal not only new insights in the cellular mechanisms underlying pathology but also new therapeutical approaches.