Telomeres and telomerase provide a unique and important avenue of study in improving both life expectancy and quality of life due to their close association with aging and disease. While major advances in our understanding of these two biological mediators have characterized the last two decades, previous studies have been limited by the inability to affect change in real time within living cells. The last three years, however, have witnessed a huge step forward to overcome this limitation. The advent of the clustered regularly interspaced short palindromic repeats/CRISPR-associated (CRISPR/Cas) system has led to a wide array of targeted genetic studies that are already being employed to modify telomeres and telomerase, as well as the genes that affect them. In this review, we analyze studies utilizing the technology to target and modify telomeres, telomerase, and their closely associated genes. We also discuss how these studies can provide insight into the biology and mechanisms that underlie aging, cancer, and other diseases.
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http://dx.doi.org/10.3390/cells8020186 | DOI Listing |
Mech Ageing Dev
January 2025
Department of Medicine, Divisions of Geriatric Medicine and Gerontology, the Department of Physiology and Biomedical Engineering, and the Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota. Electronic address:
Preclinical models of age-related osteoporosis have been developed based on the accumulation and clearance of senescent cells. The former include animal models based on telomere dysfunction and focal radiation; the latter based on genetic and pharmacological targeting (i.e.
View Article and Find Full Text PDFTo maintain genome stability, proliferating cells must enact a program of telomere maintenance. While most tumors maintain telomeres through the action of telomerase, a subset of tumors utilize a DNA-templated process termed Alternative Lengthening of Telomeres or ALT. ALT is associated with mutations in the ATRX/DAXX/H3.
View Article and Find Full Text PDFAlternative Lengthening of Telomeres (ALT) is a homologous recombination-dependent telomere elongation mechanism utilized by at least 10-15% of all cancers. Here we identified that the DNA topoisomerase, TOP3A is enriched at the telomeres of ALT cells but not at the telomeres of telomerase-positive (Tel) cancer cells. We demonstrate that TOP3A stabilizes the shelterin protein TERF2 in ALT cancer cell lines but not in Tel cells and that long non-coding telomere transcribed RNA (TERRA) enrichment at telomeres depends upon TOP3A.
View Article and Find Full Text PDFThe 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. We characterized a variable number tandem repeat within intron 6 (VNTR6-1, 38-bp repeat unit) and observed a strong association between VNTR6-1 alleles (Short: 24-27 repeats, Long: 40.
View Article and Find Full Text PDFSci Rep
January 2025
Department of Thoracic Surgery, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China.
Non-small cell lung cancer (NSCLC), half of which are lung adenocarcinoma (LUAD), is one of the most widely spread cancers in the world. Telomerase, which maintains telomere length and chromosomal integrity, enables cancer cells to avoid replicative senescence. When telomerase is inhibited, cancer cells' senescence began, preventing them from growing indefinitely.
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