研究人员在编码端粒蛋白复合物（shelterin）成分TPP1的ACD启动子中发现了一个变异群。ACD启动子变体存在于大约5%的皮肤黑色素瘤中，并与TERT启动子突变共同出现。两种最常见的体细胞变异创造或改变了E-twenty-six（ETS）转录因子的结合位点，类似于TERT启动子的突变。这些变体增加了TPP1的表达，并与TERT一起协同延长端粒的功能。这些研究结果表明，TPP1启动子变体与TERT的激活共同来加强了黑色素瘤的端粒维持和永生化。
据介绍，克服复制性衰老是肿瘤发生过程中的一个重要步骤，而通过启动子突变重新激活TERT是一个常见的机制。TERT启动子突变在大约75%的黑色素瘤中获得，但不足以维持端粒，这表明还需要额外的突变。
附：英文原文
Title: TPP1 promoter mutations cooperate with TERT promoter mutations to lengthen telomeres in melanoma
Author: Pattra Chun-on, Angela M. Hinchie, Holly C. Beale, Agustin A . Gil Silva, Elizabeth Rush, Cindy Sander, Carla J. Connelly, Brittani K.N. Seynnaeve, John M. Kirkwood, Olena M. Vaske, Carol W. Greider, Jonathan K. Alder
Issue&Volume: 2022-11-11
Abstract: Overcoming replicative senescence is an essential step during oncogenesis, and the reactivation of TERT through promoter mutations is a common mechanism. TERT promoter mutations are acquired in about 75% of melanomas but are not sufficient to maintain telomeres, suggesting that additional mutations are required. We identified a cluster of variants in the promoter of ACD encoding the shelterin component TPP1. ACD promoter variants are present in about 5% of cutaneous melanoma and co-occur with TERT promoter mutations. The two most common somatic variants create or modify binding sites for E-twenty-six (ETS) transcription factors, similar to mutations in the TERT promoter. The variants increase the expression of TPP1 and function together with TERT to synergistically lengthen telomeres. Our findings suggest that TPP1 promoter variants collaborate with TERT activation to enhance telomere maintenance and immortalization in melanoma.
DOI: abq0607
Source: https://www.science.org/doi/10.1126/science.abq0607