肿瘤细胞通过激活端粒酶或者端粒延伸替代机制（ALT）维持端粒长度，以获得持续分裂的能力。约有一半的ALT肿瘤细胞表达野生型的p53，同时还存在大量内源的DNA损伤，但是并没有引起细胞生长停滞或者凋亡，其中具体机制尚不明确。.前期工作发现具有野生型p53的ALT肿瘤细胞表现出更少的DNA损伤、更低的凋亡比例和更快的生长速度，揭示了p53具有保护ALT肿瘤细胞抵抗DNA损伤压力的功能。在此基础上本课题将从三个方面展开研究：（1）p53在DNA损伤应答中的功能；（2）p53无法诱导细胞周期停滞和凋亡的分子机制；（3）p53促进细胞生长的新机制。.本研究旨在揭示p53的新功能，阐明ALT肿瘤细胞中p53抵抗内源DNA损伤压力、促进细胞生长的分子机制。本研究不仅对认识肿瘤的发生、发展具有重要意义，同时也为ALT肿瘤治疗药物研发提供新的靶点。

To gain immortal proliferation capacity, human cancer cells maintain their telomere length through activation of telomerase or alternative lengthening of telomeres (ALT). TP53 is the most frequency mutated gene in cancer cells, but half of ALT cancer cells contain wild-type p53. Meanwhile, much endogenous DNA damage is observed in ALT cancer cells, but does not induce cell cycle arrest or apoptosis. The mechanism of DNA damage tolerance in ALT cancer is not clear..Our previous works found that ALT cancer cells with wild-type p53 show less DNA damage, lower apoptosis rate and growth faster. Interestingly, p53 protect cells against DNA damage stress in ALT cancer. Based on our previous findings, we now propose the following projects to study the mechanism of p53 novel function in ALT cancer cells: 1) p53 in DNA damage response; 2) p53 in cell cycle arrest and apoptosis; 3) p53 in cell proliferation..These studies are aimed to determine p53 novel function on DNA damage tolerance in ALT cancer cells, and generate a strong rationale for research on ALT cancer precision medicine.