保持端粒长度稳定是癌细胞克服Hayflick界限保持永生的途径。约85%的癌细胞通过端粒酶延伸端粒，另外15%的癌细胞采用端粒延伸替代途径（ALT）。通常在端粒酶阳性细胞中ALT通路被抑制。迄今为止ALT肿瘤细胞是如何产生的尚不清楚。近年来本实验室的研究表明端粒发生双链断裂（DSB）后产生了部分ALT的表征。本项目计划以此为基础研究ALT的激活。前期，我们通过CRISP/Cas9技术在端粒酶阳性细胞中产生端粒特异的DSB，观察到了ALT通路激活的全部表征。以此为细胞模型，本项目计划从以下几个方面深入研究ALT激活的机制：哪些基因的表达水平发生了变化（基因水平）；哪些信号通路被激活（蛋白网络水平）；端粒结构发生了什么变化（结构水平）。希望通过阐释ALT激活的机制为ALT肿瘤预防和治疗提供理论依据和靶点。

Cancer cells maintain telomere length in two ways to overcome hayflick limit: about 85% cancer cells use telomerase, whereas 15% cancer cells use alternative lengthening of telomeres (ALT). Usually, ALT is inhibited in telomerase cells. How does ALT activate is still unclear and attracted many researchers. Recently, results from our lab revealed that telomeric DSB could generate some of the ALT marker in telomerase positive cells. Here we set up an ALT activation cell model by generating telomeric DSB. And we plan to explore the differentially expressed genes, activated signaling pathways and telomere structural alteration during ALT activation in this model. This project is going to give a clue for prevention and therapy-treatment of ALT cancer.