酵母反转座抑制因子Rtt105在同源重组和维持基因组稳定性中的作用与机制研究

同源重组是修复DNA双链断裂的关键途径，在进化中高度保守。同源重组缺陷易导致基因组不稳定，引发癌症。在同源重组中，单链DNA（ssDNA）结合蛋白RPA及重组酶Rad51与ssDNA的动态结合对于正常修复和维持基因组稳定性至关重要，但是细胞如何调控该动态过程仍不清楚。我们前期以酵母为材料，利用遗传学、生化及单分子磁镊技术研究发现：1）缺失反转座子Ty1的抑制因子Rtt105会导致同源重组受损、自发突变和基因组不稳定性增加及对DNA损伤敏感；2）Rtt105在体内体外与RPA和Rad51相互作用；3）Rtt105在体外直接促进RPA和Rad51在ssDNA上动态组装。上述结果表明Rtt105是调控RPA及Rad51动态组装的重要因子，在同源重组和维持基因组稳定性中发挥重要作用。后续，我们将深入阐明Rtt105在上述过程中的功能与机制，为揭示人类DNA重组和基因组稳定性的调控机制提供理论借鉴。

Homologous recombination (HR) is an evolutionarily conserved key pathway for repair of DNA doube-strand breaks (DSBs). Defects in HR can cause genome instability and human cancer. During HR, dynamic assembly of the single-stranded DNA (ssDNA) binding protein RPA and the recombinase Rad51 on ssDNA is critical for proper DSB repair and maintenance of genome stability. However, how this dynamic process is regulated remains poorly understood. Here, by using a combination of genetic, biochemical and single-molecule methods, we found that: 1) yeast cells lacking Rtt105, a suppressor of Ty1 retrotransposon, exhibit impaired HR and elevated spontaneous mutation, genome instability and DNA damage sensitivity; 2) Rtt105 interacts with RPA and Rad51 both in vitro and in vivo; and 3) Rtt105 directly promotes the assembly of RPA and Rad51 on ssDNA. These results indicate that Rtt105 is a key factor regulating the dynamic assembly of RPA and Rad51 on ssDNA and is important for HR repair and the maintenance of genome stability. In future study, we aim to elucidate the function and mechanism of Rtt105 in these processes. Our study will provide insights into the regulation of HR and genome stability in human cells.