约85%的人体癌细胞通过端粒酶延伸端粒，从而获得持续的增生能力。由于端粒酶在正常的人体细胞中不表达，是特异性的抗癌靶标。研究癌细胞中端粒酶延伸端粒的分子机制具有重要的基础及应用价值。在前期的工作中我们发现：在正常生理条件下（pH=7.4），端粒酶添加~60nt TTAGGG序列到细胞每一条端粒的末端（Cell，2009）；端粒酶的延伸机制为“进行性延伸”（Mol Cell， 2011）。然而，“Warburg effect”产生的弱酸性环境是肿瘤生长的微环境，在该条件下端粒酶如何延伸端粒是领域内尚未回答的重要问题。 我们最新的研究表明，在弱酸性环境下（pH=6.8），端粒酶只延伸那些较短的端粒，预示着端粒酶作用机制的重大改变。本课题将系统研究弱酸性条件下端粒酶延伸端粒的分子机制，包括端粒酶的表达调控、端粒酶的组装及运输、端粒酶选择性延伸的分子机制、端粒结合蛋白对端粒酶延伸的影响等。

To gain immortal proliferation capacity, ~85% human cancer cells maintain their telomere length through activation of telomerase. Because human normal somatic cells don’t express telomerase, telomerase is considered as a specific anti-cancer target. An understanding of telomerase action in cancer cells thus has important implication for both basic biology and clinical application. Our previous works found that under normal physiological condition (pH=7.4) telomerase add ~60nt to every telomere end in cells (Cell, 2009), and that telomerase action is “processive”(Mol Cell. 2011). However, because of “Warburg effect”, acidic pH is an actual microenvironment for tumor growth. Unanswered question in telomere biology concerns how telomerase maintains telomere length under acidic pH. Our new data show that under acidic pH (pH=6.8) telomerase preferentially extend the shortest telomeres, indicating fundamental difference in telomerase extension between physiological and acidic pH. This project will investigate the mechanism underlying telomere extension by telomerase under acidic pH, including expression regulation of telomerase, telomerase assembly and trafficking, the machinery that determines the preferential extension of the shortest telomeres by telomerase and the effect of telomere binding proteins on telomerase action.