hSSB1是重要的单链DNA结合蛋白，其缺失导致细胞周期检测点失活，基因组不稳定及放化疗敏感性增加，表明hSSB1是一个潜在的肿瘤治疗靶点。但其被调控的机制尚未明确。我们研究表明，hSSB1既可结合并促进p21及p53蛋白稳定性，又可与p300相互作用，促进p300对p53的382位赖氨酸的乙酰化，增强p53对p21的转录激活作用。最近预实验发现：hSSB1也可被p300乙酰化，且在DNA损伤应激情况下，其乙酰化水平呈时间和剂量依赖性增加；去乙酰化酶抑制剂TSA和NAM单独或联合处理，可促进hSSB1乙酰化表达水平的升高。本项目拟鉴定hSSB1被p300乙酰化的位点，及其去乙酰转移酶；明确p300与hSSB1的相互作用机制；揭示hSSB1乙酰化的生物学功能和临床意义。本项目的完成，将阐明p300对hSSB1乙酰化调控的机制和意义，为p300抑制剂作为放化疗增敏剂在临床上的应用提供实验依据。

Human single-strand DNA binding proteins 1 (hSSB1) has been shown to participate in the DNA damage response. Cells deficient in hSSB1 exhibit defective cell cycle checkpoint activation, increased radiosensitivity and enhanced genomic instability, indicating that hSSB1 may be a therapeutic target. However, the regulaiton of hSSB1 remains elusive. We have provided evidence that hSSB1can interact with both p53 and p21, to protects p53 and p21 from ubiquitin-mediated degradation. Furthermore, hSSB1 associates with the acetyltransferase p300 and is required for efficient transcriptional activation of the p53 target gene p21 by affecting the acetylation of p53 at lysine382. In fact, we recently found that hSSB1 could be acetylated by p300, and this acetylation of hSSB1 were increased in a dose- and time-dependent manner; TSA and NAM, both deacetylation inhibitors, were capable of increasing the acetylation of hSSB1 when they were used alone or combination. This proposal here will continue to investigate following events: To identify the acetylation site of hSSB1 and the deacetyltransferase(s) involved in this acetylation of hSSB1; To investigate the mechanism of interaction between hSSB1 and p300; To determine the biological and clinical significance of this acetylation of hSSB1. At the end of this proposal, we will demonstrate the mechanism and significance of hSSB1 acetylation by p300, and will provide evidence to further support the notion that p300 inhibitors may be used as the sensitizer for chemo- or radiotherapy in patients with cancers.