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Polymorphic tandem DNA repeats activate the human telomerase reverse transcriptase gene

Significance Repetitive DNA sequences are abundant in the human genome, and their high variabilities contribute to genetic diversity and disease susceptibility. Here, we report that an intronic variable number tandem repeat element, VNTR2-1, is critical for the transcription of the human telomerase reverse transcriptase (hTERT) gene in a cell-context–dependent manner. Removal of this element at its native genomic site in cancer cells resulted in telomere shortening, cellular senescence, and impaired tumor growth. VNTR2-1 length, consisting of 53 to 160 copies of 42-bp repeats, varies widely in human populations. hTERT alleles with short VNTR2-1 are underrepresented in African American centenarians, suggesting that hTERT regulation by VNTR2-1 plays a role in human aging and tumorigenesis. 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.