The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Hunan Normal University School of Medicine, Changsha, Hunan, China.
Center for Reproduction and Genetics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, China.
J Biol Chem. 2023 Sep;299(9):105053. doi: 10.1016/j.jbc.2023.105053. Epub 2023 Jul 15.
Alternative lengthening of telomeres (ALTs) mechanism is activated in some somatic, germ cells, and human cancer cells. However, the key regulators and mechanisms of the ALT pathway remain elusive. Here we demonstrated that ZBTB40 is a novel telomere-associated protein and binds to telomeric dsDNA through its N-terminal BTB (BR-C, ttk and bab) or POZ (Pox virus and Zinc finger) domain in ALT cells. Notably, the knockout or knockdown of ZBTB40 resulted in the telomere dysfunction-induced foci and telomere lengthening in the ALT cells. The results also show that ZBTB40 is associated with ALT-associated promyelocytic leukemia nuclear bodies, and the loss of ZBTB40 induces the accumulation of the ALT-associated promyelocytic leukemia nuclear bodies in U2OS cells. Taken together, our results implicate that ZBTB40 is a key player of telomere protection and telomere lengthening regulation in human ALT cells.
端粒的非经典延长（ALT）机制在一些体细胞、生殖细胞和人类癌细胞中被激活。然而，ALT 途径的关键调节因子和机制仍不清楚。在这里，我们证明 ZBTB40 是一种新型的端粒相关蛋白，通过其 N 端 BTB（BR-C、ttk 和 bab）或 POZ（痘病毒和锌指）结构域与 ALT 细胞中的端粒 dsDNA 结合。值得注意的是，ZBTB40 的敲除或敲低导致 ALT 细胞中端粒功能障碍诱导的焦点和端粒延长。结果还表明，ZBTB40 与 ALT 相关早幼粒细胞白血病核体相关，ZBTB40 的缺失诱导 U2OS 细胞中 ALT 相关早幼粒细胞白血病核体的积累。总之，我们的结果表明 ZBTB40 是人类 ALT 细胞中端粒保护和端粒延长调节的关键参与者。
