端粒延伸过程中C链合成（C-rich Fill-in）的分子机理

最新的研究发现癌细胞中端粒的延伸分为两个相对独立的过程：在细胞周期的整个S期，端粒酶添加～60nt的TTAGGG序列到每一条端粒的末端；而其互补链C-rich链的合成（C-rich Fill-in）则发生在S期后期和G2期。这两个过程缺一不可，对于维持癌细胞中端粒的长度具有同等重要的意义。然而我们对于C-rich Fill-in的合成机制了解甚少。我们前期的研究表明，C-rich Fill-in中DNA的合成是不连续的，并受到多个端粒结合蛋白的调节。由于在Late S/G2大量与DNA损伤修复相关的蛋白质定位到染色体末端，我们推测：DNA损伤修复机制参与了C-rich Fill-in的信号传导和DNA合成。本课题将系统研究激活C-rich Fill-in的信号通路及其DNA合成的分子机理，并阐明端粒结合蛋白对C-rich Fill-in的调节作用。

Recent studies found that the telomere extension in cancer cells involves two independent processes: telomerase add ～60nt of TTAGGG sequence to each telomere end during S phase of cell cycle and the synthesis of its complementary strand (C-rich Fill-in) that only occurs at late S and G2 phase. Two events are equally important for telomere length maintenance of cancer cells. However, we know extremely little about how C-rich Fill-in is carried out. Our preliminary studies suggested an incremental DNA synthesis of C-rich Fill-in that is regulated by multiple telomere binding proteins. Given the fact that large numbers of proteins involved in DNA damage repair (DDR) are positioned to telomeres at late S/G2, we proposed that DDR proteins participate in the signal transduction and DNA synthesis of C-rich Fill-in. This project will investigate the signal pathway that activates C-rich Fill-in and the mechanism underlying C-strand DNA synthesis. Furthermore, we will study how telomere binding proteins regulate C-rich Fill-in in Late S/G2.