题目：RESCUING REPLICATION: ROLE OF HUMAN CST AT TELOMERES AND BEYOND

时间：2013年10月29日星期二，上午10：00至11：30

地点：中山大学（大学城）行政楼B座一层讲学厅（B101）

主讲人：Carolyn M. Price教授

主持人：松阳洲教授

（ Carolyn M. Price教授拟在中国招收博士后，欢迎有意向者于【10月30日9:30-11:00】到东校区生科院501会议室进行交流）

主讲人简介：

Dr. Carolyn M. Price, professor at Department of Cancer and Cell Biology at University of Cincinnati. Her research focuses on studying the structure and composition of the telomeric DNA-protein complex and mechanisms of telomere replication in both vertebrate cells and ciliates. She has published many papers in leading scientific journals including Nature, Science, Nat. Str. Mol. Biol, Gene & Development, Mol Cell, PNAS and has received numerous awards including Chromosoma Prize for the outstanding paper of the year, NSF Career Advancement Award and so on. She has served as Ad hoc reviewer for the National Science Foundation and provide occasional reviews for Science Foundation around the world, including the Israeli Science Foundation, Cancer Research UK, the German Science Foundation, French CNRS ATIP, the Philip Morris Foundation, and Human Frontiers of Science.

 摘要：

Human CST (CTC1-STN1-TEN1) is an RPA-like complex that resembles the Cdc13-Stn1-Ten1 complex which is responsible for telomere protection in budding yeast. Mutations in the CTC1 subunit of CST cause Coats plus, a severe disorder that causes neurological symptoms and premature death. Like yeast Cdc13-Stn1-Ten1, mammalian CST associates with telomeres and knockdown of CTC1, STN1 or TEN1 causes telomere defects. However in mammalian cells, the six subunit shelterin complex is responsible for telomere protection and CST appears to function as a specialized replication factor both at telomeres and elsewhere in the genome. We have found that CST plays two independent roles in telomere replication. First, CST facilitates passage of the replication fork through the telomere duplex DNA. Since telomeres act as a natural barrier to the replication machinery, it is likely that the role of CST is to restart replication after fork stalling within the telomere duplex. Second, CST is needed for the C-strand fill-in synthesis reaction that occurs in G2/M after telomerase extends the telomeric G-strand. This fill-in reaction is essential to convert the ssDNA synthesized by telomerase into the dsDNA needed to maintain telomere length. In addition to these telomeric functions, we have shown that CST is needed to resolve replication problems throughout the genome. Cells depleted of CST exhibit genomic instability and are sensitive to a variety of drugs that stall replication forks. Following HU treatment, CST helps restart replication by promoting the firing of dormant replication origins. Our work identifies CST as a novel replication factor that solves multiple replication-associated problems, most likely by enabling DNA synthesis to initiate in situations where the replisome is absent or damaged. Mutation of the STN1 subunit affects some but not all CST functions indicating that the mechanism of action is modified by location and type of replication stress. We propose that the wider range of symptoms observed in patients with CTC1 mutation/Coats plus as compared the short telomere syndromes caused by telomerase mutation may reflect the role of CST in resolving more diverse replication-related problems.