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Title: Polymorphic tandem DNA repeats activate the human telomerase reverse transcriptase gene.

Authors: Xu, Tao; Cheng, De; Zhao, Yuanjun; Zhang, Jinglong; Zhu, Xiaolu; Zhang, Fan; Chen, Gang; Wang, Yang; Yan, Xiufeng; Robertson, Gavin P; Gaddameedhi, Shobhan; Lazarus, Philip; Wang, Shuwen; Zhu, Jiyue

Published In Proc Natl Acad Sci U S A, (2021 06 29)

Abstract: Multiple independent sequence variants of the hTERT locus have been associated with telomere length and cancer risks in genome-wide association studies. Here, we identified an intronic variable number tandem repeat, VNTR2-1, as an enhancer-like element, which activated hTERT transcription in a cell in a chromatin-dependent manner. VNTR2-1, consisting of 42-bp repeats with an array of enhancer boxes, cooperated with the proximal promoter in the regulation of hTERT transcription by basic helix-loop-helix transcription factors and maintained hTERT expression during embryonic stem-cell differentiation. Genomic deletion of VNTR2-1 in MelJuSo melanoma cells markedly reduced hTERT transcription, leading to telomere shortening, cellular senescence, and impairment of xenograft tumor growth. Interestingly, VNTR2-1 lengths varied widely in human populations; hTERT alleles with shorter VNTR2-1 were underrepresented in African American centenarians, indicating its role in human aging. Therefore, this polymorphic element is likely a missing link in the telomerase regulatory network and a molecular basis for genetic diversities of telomere homeostasis and age-related disease susceptibilities.

PubMed ID: 34155099 Exiting the NIEHS site

MeSH Terms: African Americans/genetics; Aged, 80 and over; Animals; Base Sequence; Cell Differentiation/genetics; Cell Line; Cell Proliferation/genetics; Chromosomes, Artificial, Bacterial/genetics; E-Box Elements/genetics; Genome, Human; Human Embryonic Stem Cells/metabolism; Humans; Mice, Nude; Minisatellite Repeats/genetics*; Neoplasms/genetics; Neoplasms/pathology; Polymorphism, Genetic*; Promoter Regions, Genetic; Protein Binding/genetics; Sequence Deletion/genetics; Telomerase/genetics*; Telomere Homeostasis/genetics; Transcriptional Activation*

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