FUNCTION OF MITOTIC SUMOYLATION ON GENOMIC INSTABILITY

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 细胞分裂的基本功能之一是基因组DNA的复制和分离。复制的基因组DNA在细胞分裂的有丝分裂过程中均匀分离，以保持完整的基因组信息。与有丝分裂中基因组DNA分离特别相关的问题在理解脊椎动物细胞的基础生物学和解决由基因组DNA分离的错误调节导致基因组不稳定性引起的人类癌症的分子基础方面都是重要的。实现忠实有丝分裂的一个关键因素是蛋白质的修饰。最近的研究表明，SUMO（小泛素样调节剂）对蛋白质的修饰在有丝分裂过程中染色体的正确分离中起着至关重要的作用。因此，了解SUMO化在有丝分裂过程中的功能将为预防基因组不稳定性提供新的信息，并有望改善癌症预防的治疗方法。为了实现这一目标，我已经确定DNA拓扑异构酶II（TopoII）作为一个主要的有丝分裂特异性SUMO化蛋白。为了了解拓扑II SUMO化的功能，我建议确定潜在的结合伙伴，其协会拓扑II是由这种修改，这将调节有丝分裂染色体的组织，将需要正常分离的染色体。我已经从有丝分裂染色体中分离出两种新的SUMO化蛋白。这些新的SUMO化的蛋白质预期在染色体分离中与TopoII的SUMO化一起具有重要作用。通过本研究的结果，我将深入了解SUMO修饰在有丝分裂和有丝分裂染色体调控中的作用。新的信息将提供更好的理解，以防止染色体不稳定性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. One of the fundamental functions of cell division is the duplication and separation of genomic DNA. Replicated genome DNA is evenly segregated during mitosis of cell division to maintain complete genomic information. Questions specifically related to separation of genomic DNA in mitosis are important both in understanding the fundamental biology of vertebrate cells and in addressing the molecular basis of human cancers caused by mis-regulation of genomic DNA separation resulting in genomic instability. One key element in achievement of faithful mitosis is modifications of proteins. Recent studies indicate that the protein modification by SUMO, Small Ubiquitin-like MOdifier, plays a crucial role in proper chromosomal separation during mitosis. Therefore, understanding the function of SUMOylation during mitosis will provide novel information to prevent genomic instability and is expected to improve therapeutics for cancer prevention. Toward that goal, I have identified DNA topoisomerase II (TopoII) as a major mitotic-specific SUMOylatiod protein. To understand the function of SUMOylation of TopoII, I propose to identify potential binding partners whose association to TopoII is regulated by this modification, which will regulate mitotic-chromosomal organization that will be required for normal separation of chromosomes. I have isolated two novel SUMOylated proteins from mitotic chromosomes. These novel SUMOylated proteins are expected to have an important role in chromosome segregation together with SUMOylation of TopoII. Through the results obtained from this proposal, I will gain insight into the consequences of SUMO modification during mitosis and regulation of mitotic chromosomes. The novel information will provide better understanding to prevent chromosomal instability.