| Title: | Genetic regulation of TERT splicing affects cancer risk by altering cellular longevity and replicative potential |
| Journal: | Nature Communications |
| Published: | 16 Feb 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39956830/ |
| DOI: | https://doi.org/10.1038/s41467-025-56947-y |
Publication 14387
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Abstract
The chromosome 5p15.33 region, which encodes telomerase reverse transcriptase (TERT), harbors multiple germline variants identified by genome-wide association studies (GWAS) as risk for some cancers but protective for others. Here, we characterize a variable number tandem repeat within TERT intron 6, VNTR6-1 (38-bp repeat unit), and detect a strong link between VNTR6-1 alleles (Short: 24-27 repeats, Long: 40.5-66.5 repeats) and GWAS signals rs2242652 and rs10069690 within TERT intron 4. Bioinformatics analyses reveal that rs10069690-T allele increases intron 4 retention while VNTR6-1-Long allele expands a polymorphic G-quadruplex (G4, 35-113 copies) within intron 6, with both variants contributing to variable TERT expression through alternative splicing and nonsense-mediated decay. In two cell lines, CRISPR/Cas9 deletion of VNTR6-1 increases the ratio of TERT-full-length (FL) to the alternative TERT-β isoform, promoting apoptosis and reducing cell proliferation. In contrast, treatment with G4-stabilizing ligands shifts splicing from TERT-FL to TERT-β isoform, implicating VNTR6-1 as a splicing switch. We associate the functional variants VNTR6-1, rs10069690, and their haplotypes with multi-cancer risk and age-related telomere shortening. By regulating TERT splicing, these variants may contribute to fine-tuning cellular longevity and replicative potential in the context of stress due to tissue-specific endogenous and exogenous exposures, thereby influencing the cancer risk conferred by this locus.</p>
15 Keywords
- Alleles
- Alternative Splicing
- Apoptosis
- CRISPR-Cas Systems
- Cell Line, Tumor
- Cell Proliferation
- G-Quadruplexes
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Humans
- Introns
- Minisatellite Repeats
- Neoplasms
- Polymorphism, Single Nucleotide
- Telomerase
23 Authors
- Oscar Florez-Vargas
- Michelle Ho
- Maxwell H. Hogshead
- Brenen W. Papenberg
- Chia-Han Lee
- Kaitlin Forsythe
- Kristine Jones
- Wen Luo
- Kedest Teshome
- Cornelis Blauwendraat
- Kimberly J. Billingsley
- Mikhail Kolmogorov
- Melissa Meredith
- Benedict Paten
- Raj Chari
- Chi Zhang
- John S. Schneekloth
- Mitchell J. Machiela
- Stephen J. Chanock
- Shahinaz M. Gadalla
- Sharon A. Savage
- Sam M. Mbulaiteye
- Ludmila Prokunina-Olsson
1 Application
| Application ID | Title |
|---|---|
| 92005 | Integrative analysis of genomic, molecular, cellular, and biochemical measures to inform cancer etiology |
Enabling scientific discoveries that improve human health