Polymorphic tandem DNA repeats activate the human telomerase reverse transcriptase gene

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

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7 Scopus citations


Multiple independent sequence variants of the hTERT locus have been associated with telomere length and cancer risks in genomewide 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.

Original languageEnglish (US)
Article numbere2019043118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number26
StatePublished - Jun 29 2021

All Science Journal Classification (ASJC) codes

  • General


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