基因组稳定性(genome stability)与肿瘤发生密切相关。在细胞有丝分裂的过程中，基因组稳定性受到黏连蛋白(Cohesin)及其相关基因的调控，这些基因的突变、缺失以及其他异常将导致基因组不稳定。目前，黏连蛋白及其相关基因控制基因组稳定性的具体作用机制尚不清楚。本课题的前期研究发现黏连蛋白及其相关基因的突变可导致DNA复制起点的选择发生变化，并使DNA复制的速率下降。同时，我们发现大量与dNTP代谢有关蛋白水平发生了变化。我们推测黏连蛋白通过调节dNTP相关基因代谢影响了DNA，并影响DNA复制。为证明该推测，我们将应用流式细胞技术、脉冲场凝胶电泳、高效液相色谱、荧光显微镜技术以及深度测序等多种技术，研究不同黏连蛋白突变体对DNA复制和基因组稳定性机制的影响，为针对黏连蛋白为靶点的肿瘤治疗提供理论依据。

Genome stability is closely related to carcinogenesis. During mitosis, genome stability is regulated by cohesin complex and its related genes. Mutations or deletions of these genes have been found to cause genome instability. However, the mechanism of how cohesin regulates genome stability is still unknown. Our previous study has shown that mutations of cohesin and its related genes caused different pattern of DNA replication origin choice and reduced the speed of DNA replication. We also found that the protein levels of the genes related with nucleotide metabolism are alternated in the cohesin mutants. We propose the hypothesis that alternation of dNTP levels in cohesin mutants will cause DNA replication defect, which will further lead to genome instability. To test our hypothesis, we designed multiple methods to study the role cohesin complex in maintaining genome stability in this proposal. We hope that our study will shed light on the application of cohesin as a target in tumor therapy.