核孔蛋白Tpr和Nup153在微核内染色体粉碎化发生过程中的作用研究

最近提出的“染色体碎裂”系指局限于单条染色体（或臂）上拷贝数变化类型有限的大规模染色体重排。目前认为其可能是“单次打击”致肿瘤突然发生的原因。最新研究发现微核染色体粉碎化重新整合入基因组可能是它发生的主要形成机制。微核中粉碎化染色体的形成机制尚不清楚。研究提示有丝分裂纺锤体检查点机制受损可以导致带着丝粒的微核染色体发生损伤甚至粉碎化，而核孔蛋白Tpr和Nup153在该调控机制中可以通过调控Mad1/Mad2复合体以及53BP1定位影响染色体错误分离及DNA的损伤修复，所以我们推测在化学物/诱变剂作用下，核孔蛋白Tpr和Nup153异常可以导致微核形成和内部染色体损伤，而且使损伤得不到及时修复，在微核染色体粉碎化过程中发挥关键作用。本课题将通过构建多种微核细胞模型，研究核孔蛋白Tpr和Nup153在微核形成及内部DNA损伤修复中的功能和作用，为微核-染色体碎裂导致肿瘤发生的机制提供有效线索。

The chromothripisis, discovered in multiple tumor cells recently, refers to a chromosomal rearrangement event defined in one single chromosome, with limited copy number change types. It is a challenge to the traditional evolutionary tumorgenesis theory. Micronucleation and chromosome pulverization within micronuclei are recognized as the main machanism of this event. The mechanism underlying the pulverized segments in micronuclei remains unclear. Several studies indicate that abnormal function of mitosis spindle checkpoint mechanism could induce damage in the cetromered chromosomes within micronuclei. Since nucleoporins Tpr and Nup153 play a key role in this process, inducing both missegregation and abnormal chromosomal damage as well as repair, we speculated that the malfunction of Tpr and Nup153 could lead to micronucleation and pulverization within micronuclei in the chemical/mutagen treated cells. The project will study the function and the role of nucleoporins Tpr and Nup153 in the formation of micronuclei and DNA damage and repair activities within micronuclei through construction of multiple micronucleating models, therefore providing effective clues for the study of micronucleus-chromothripisis to tumor mechanism.