Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Curr Opin Genet Dev. 2020 Feb;60:56-62. doi: 10.1016/j.gde.2020.02.001. Epub 2020 Mar 9.
Telomerase regulation and telomere shortening act as a strong tumor suppressor mechanism in human somatic cells. Point mutations in the promoter of telomerase reverse transcriptase (TERT) are the most frequent non-coding mutation in cancer. These TERT promoter mutations (TPMs) create de novo ETS factor binding sites upstream of the start codon of the gene, which can be bound by different ETS factors. TPMs can occur early during tumorigenesis and are thought to be among the first mutations in melanoma, glioblastoma and hepatocellular carcinoma. Despite their association with increased TERT levels, TPMs do not prohibit telomere shortening and TPM-harboring cancers present with short telomeres. Their short telomere length combined with their high prevalence and specificity for cancer makes TPMs an attractive target for future therapeutic exploitation of telomerase inhibition and telomere deprotection-induced cell death.
端粒酶调节和端粒缩短是人类体细胞中一种强大的肿瘤抑制机制。端粒酶逆转录酶（TERT）启动子中的点突变是癌症中最常见的非编码突变。这些 TERT 启动子突变（TPM）在上游基因起始密码子处创建新的 ETS 因子结合位点，这些结合位点可被不同的 ETS 因子结合。TPM 可能在肿瘤发生的早期发生，并且被认为是黑色素瘤、胶质母细胞瘤和肝细胞癌中最早的突变之一。尽管 TPM 与 TERT 水平升高有关，但它们并不阻止端粒缩短，并且携带 TPM 的癌症具有短的端粒。它们的短端粒长度与其在癌症中的高发生率和特异性相结合，使得 TPM 成为未来端粒酶抑制和端粒去保护诱导细胞死亡治疗开发的有吸引力的靶点。
