SOSS1复合体在DNA双链断裂修复过程中结合ssDNA及其它蛋白质的分子机制研究

DNA double-strand breaks (DSBs) are highly toxic and can cause genome rearrangement and cell death. Defective DSB repair can cause cancer, neurodegenerative disorders, immune deficiencies, cardiovascular disease and metabolic syndrome. One of the pathways to repair DSB is homologous recombination (HR), which involves the resection of DSBs to generate a 3'-single-stranded DNA (ssDNA) overhang. ssDNA binding proteins(SSBs) are crucial for the protection of ssDNA and DSB signaling. Studies on them would provide fundamental insights into the mechanism of DSB repair. Recently, two ssDNA binding proteins SOSSB1 and SOSSB2 were reported to function at DSBs to form two separate heterotrimeric complexes with SOSSA and SOSSC, termed SOSS1 and SOSS2, respectively. SOSS1 and SOSS2 sense ssDNA and promote DSB repair and checkpoint activation. In this study, we will primarily use X-ray crystallography in conjunction with biophysical, biochemical, molecular and cell biology approaches to study the mechanism by which the SOSS1 complex recognizes ssDNA and interacts with other proteins during DSB repair.

DNA双链断裂(DSB)可能导致基因组重排和细胞死亡, 是最具有细胞毒性的DNA损伤方式之一。有缺陷的DSB修复将导致机体癌变、神经退行性疾病、免疫缺陷、心血管疾病以及一些代谢性综合症。同源重组(HR)是最有效的一种DSB修复方式。HR起始于在损伤处切割形成3'单链DNA(ssDNA)。ssDNA结合蛋白结合并保护暴露的ssDNA，同时参与DSB修复的信号传导。对该类蛋白进行结构和功能的研究将为阐释DSB修复的分子机理奠定坚实基础。最新研究发现单链DNA结合蛋白SOSSB1(hSSB1)和SOSSB2(hSSB2)，可通过与SOSSA和SOSSC分别形成SOSS1和SOSS2复合体，参与DSB修复。本项目主要利用X-射线晶体衍射技术， 结合生物化学、生物物理及分子与细胞生物学的方法，研究SOSS1复合体识别ssDNA及与其他蛋白质的分子机制，阐明SOSS1复合体在DSB修复中的作用机制。