在DNA损伤修复中组蛋白修饰的缺陷可诱发基因组不稳定性进而导致肿瘤发生。在前期工作中，我们发现PTEN通过其类泛素化（SUMOylation）修饰可能调控DNA损伤应答（DDR）中组蛋白的修饰，进而影响前列腺癌的发生发展。本项目将深入研究在DDR中SUMO-PTEN的新功能及分子机制：DNA损伤促进PTEN SUMO化可使其结合到DNA损伤附近的染色质组蛋白上。在DNA断裂较远端处，SUMO-PTEN招募EZH2/PRC2，提高H3K27me3的水平而阻止基因转录；同时，在DNA损伤最近端处，SUMO-PTEN则招募BAP1/PR-DUB，去除H2AK119的单泛素化而允许对DNA损伤进行直接修复。还将构建SUMO位点突变的PTEN敲入、EZH2/BAP1/PTEN敲除的小鼠前列腺模型及分析临床前列腺癌中三个基因的突变与表达情况，以期阐明PTEN在DDR与前列腺癌发生发展中的功能及生理意义

Histone modification defects in DNA damage repair can induce genomic instability leading tumorigenesis. In our preliminary work we found that PTEN may regulate histone modifications in DNA damage response (DDR) through its SUMOylation, thereby influencing prostate cancer development. The project will further focus on the new features and molecular mechanisms of SUMO-PTEN in DDR: SUMO modification of PTEN induced by DNA damage promotes it to bind to chromatin histones nearby DNA damage. At the distal to DNA break (such as DSB), SUMO-PTEN can recruit EZH2/PRC2 (Polycomb-group repressive complex 2) to increase the level of H3K27me3, thus preventing gene transcription. At the same time, at the proximity of DNA break SUMO-PTEN can recurit BAP1/PR-DUB (Polycomb repressive deubiquitinase) to remove the monoubiquitination of H2A on K119 residue (H2Aub), thus allowing the recruitment of downstream DNA break signaling and repair proteins. We will also construct the SUMO-site point mutated PTEN knock-in and EZH2/BAP1/PTEN knockout mouse prostate models and analyze the mutations and expression levels of these three genes in clinical prostate cancer samples, in order to clarify the function and physiological significance of PTEN in DDR and prostate cancer development.