染色质重塑与基因转录调控、DNA损伤应答有着密切的联系。DNA双链断裂(DSBs)后，其附近的转录被抑制，然而具体机制不明。我们近期研究发现：1) 染色质重塑复合物亚基SNF5参与DNA损伤诱导的转录抑制；2) 机制上，SNF5通过增强招募PRC2转录抑制复合物到DSBs处，导致DSBs处H3K27me3增加，进一步募集PRC1复合物，最终导致H2AK119Ub上升，实现转录抑制；3)上述功能的发挥依赖于ATM介导的SNF5 第120位Ser磷酸化信号；4) SNF5的缺失导致HR修复能力下降，使细胞对放化疗更加敏感。由此我们提出科学假设：SNF5通过ATM依赖的磷酸化直接招募PRC2复合物促进转录抑制。本研究将详尽阐明SNF5调控DSBs诱导转录抑制及参与HR修复的分子机制，并在细胞、动物水平揭示ATM-SNF5-PRC2通路在乳腺癌中的意义，为乳腺癌的诊断及靶向治疗提供新的理论基础。

Chromatin remodeling mediated gene transcription regulation and DNA damage response are tightly coordinated. Recent studies indicate that transcription is repressed in response to neighboring DNA double-strand breaks (DSBs). However, little is known about the mechanism that links DNA damage responses and nascent transcription on a contiguous stretch of chromatin. Recent studies have demonstrated that SNF5, a subunit of SWI/SNF chromatin remodeling complex, is recruited to DNA damage sites, and promotes transcriptional silencing and homologous recombination depending on the interaction with PRC2 complex. Further more, ATM phosphorylates SNF5 at ser 120 to recruit it to DNA double-strand break(DSB) sites in response to DNA damage. Functional study indicated that SNF5 depletion or mutation rendered cells more sensitive toward chemotherapy and radiotherapy in HeLa and MDA-MB-231 cell. Taken together, we may conclude that kinase ATM mediated SNF5 phosphorylation enhances the interaction between SNF5 and PRC2 complex, which promotes transcriptional silencing and homologous recombination repair. In this project, we will clarify the detailed mechanism of SNF5 in repressing transcription and facilitating HR repair, and uncover the oncology significance of ATM-SNF5-PRC2 pathway in vivo and in vitro, and providing novel theoretical basis for individualized targeted therapy in breast cancer.