TERT 启动子内的点突变是在不同癌症类型中发现的最常见的体细胞非编码突变，包括胶质母细胞瘤、黑色素瘤、肝细胞癌和膀胱癌。它们在-146C>T和-124C>T时最丰富，在-57A>C时较少，后者最初被描述为家族病例，但随后显示也发生在体细胞上。所有三种突变都会从头产生 ETS（E-26 特异性）结合位点，并导致 TERT 基因激活，从而使癌细胞实现复制永生。在这里，我们采用系统的蛋白质组学筛选来鉴定优先结合-146C>T、-124C>T和-57A>C突变的转录因子。虽然我们确认了多个 ETS 因子与突变体 -146C>T 和 -124C>T 序列的结合，但我们将 E4F1 鉴定为 -57A>C 特异性结合物，将 ZNF148 鉴定为 TERT 野生型启动子结合物，显示与突变体的相互作用减少。 -124C>T等位基因。这两种蛋白都是激活转录因子，特异性结合相应细胞系中的 -57A>C 和野生型（第 124 位）TERT 启动子序列，并上调 TERT 转录和端粒酶活性。我们的工作描述了 TERT 基因表达的新调节因子在癌症中的可能作用。由冷泉港实验室出版社出版。

Point mutations within the TERT promoter are the most recurrent somatic noncoding mutations identified across different cancer types, including glioblastoma, melanoma, hepatocellular carcinoma, and bladder cancer. They are most abundant at -146C>T and -124C>T and rarer at -57A>C, with the latter originally described as a familial case, but subsequently shown also to occur somatically. All three mutations create de novo ETS (E-twenty-six specific) binding sites and result in activation of the TERT gene, allowing cancer cells to achieve replicative immortality. Here, we employed a systematic proteomics screen to identify transcription factors preferentially binding to the -146C>T, -124C>T and -57A>C mutations. While we confirmed binding of multiple ETS factors to the mutant -146C>T and -124C>T sequences, we identified E4F1 as an -57A>C-specific binder and ZNF148 as a TERT wild-type promoter binder that showed reduced interaction with the -124C>T allele. Both proteins are activating transcription factors that bind specifically to the -57A>C and wild-type (at position 124) TERT promoter sequence in corresponding cell lines and upregulate TERT transcription and telomerase activity. Our work describes new regulators of TERT gene expression with possible roles in cancer.Published by Cold Spring Harbor Laboratory Press.