在整个生命周期里生物体不断与周遭环境互相影响。多种环境胁迫因素都能导致DNA的损伤，引起细胞提前衰老、死亡以及癌症的发生。由于与高度动态且复杂的转录机器相偶联，转录偶联DNA损伤修复的研究较为模糊，存在自相矛盾的观点。我们前期的研究提示，细胞内存在两个CSB，即CSB/Histone和CSB/PolII，前者通过CSB识别并结合H3K79甲基化执行TCR复合体的组装和DNA损伤修复的功能。CSB或RPA先各自形成“一半TCR复合体”，再结合到组蛋白上快速组装成完整的TCR复合体，实现DNA损伤的高效修复。借鉴该理论模型，我们发现干扰CSB与H3K79甲基化的相互作用可能有潜在的化疗增敏效果。因此，本项目拟在前期积累的基础上，深入研究双CSB调控TCR的功能和分子机制。通过本项目的研究，我们希望找到一种合适的化疗增敏策略，指导临床实践。

Living organisms are constantly threatened by environmental agents and endogenous byproducts from cellular metabolic processes throughout their life. Many risk factors can cause DNA damage that affects the integrity of DNA thereby promote premature aging, cell death or carcinogenesis. Due to the coupling of the complex DNA damage repair process with the dynamic and intricate transcriptional machinery, knowledge on transcription-coupled repair remain largely contradictory and unclear. Our previous studies suggest that there are dual CSB complexes in the cell, namely CSB/Histone and CSB/Pol II, with the former performing the assembly of TCR-associated complex and DNA damage repair through the recognition and consequent interaction with H3K79 methylation by CSB. CSB and RPA first form two halves of the TCR complex, then rapidly bind together on histones to generate the complete TCR complex for efficient repair of DNA damage. Drawing from this theoretical model, we find that disrupting the interaction between CSB and H3K79 methylation may have potential chemotherapy sensitization effects. Therefore, this project intends to elucidate the function and molecular mechanism of the control of TCR by dual CSBs. Our final goal is to explore a novel chemotherapy sensitization strategy based on this project and apply it to clinical trials.