DNA损伤所致基因突变是癌症发生的主要原因。染色体中间区域的端粒序列（TSI）会使染色体易于断裂、重排和重组，增加基因组不稳定性，诱发肿瘤。我们的前期工作表明，错配修复蛋白MLH1可以端粒酶依赖地抑制TSI插入到染色体中间部位，代表一种全新的基因组稳定性维持机制。本课题拟围绕MLH1抑制TSI的分子机制，阐明MLH1抑制TSI的相关关键结构域、端粒特异结合蛋白对TSI的影响和关键分子事件；研究其它错配修复蛋白抑制TSI的能力；探索TSI的形成机制研究。本研究旨在揭示MLH1等错配修复蛋白抑制TSI的具体机制和TSI的发生机制，推动肿瘤发病机制研究，为癌症的预防、早期发现和治疗提供理论研究基础。

Gene mutations induced by DNA damage is one of the major cause of cancer. Telomeric sequences insertion (TSI) at intro-chromosome are prone to chromosome breakage, recombination and rearrangement that increase genomic instability and lead to tumor ultimately. Our previous studies demonstrated that mismatch repair protein, MLH1 suppressed telomeric sequences insertion at internal genome sites that is dependent on telomerase. The finding represents a new mechanism of maintaining genome stability. The aims of this proposed work are to determine : the molecular mechanism of TSI suppression; clarifying the key structure domain of MLH1 inhibiting TSI, the key molecular events and effect of telomeric specific binding proteins on TSI; studying the inhibition ability of other mismatch repair proteins to TSI; exploring the mechanism of TSI formation. This project aims at revealing the mechanism of TSI formation and TSI inhibition by mismatch repair proteins including MLH1, moving forward with the studying of tumorigenesis mechanism and provides a good base for prevention, early detection and treatment of cancer.