Abstract
The accumulated evidence has pointed to a key role of telomerase in carcinogenesis. As a RNA-dependent DNA polymerase, telomerase synthesizes telomeric DNA at the end of linear chromosomes, and attenuates or prevents telomere erosion associated with cell divisions. By lengthening telomeres, telomerase extends cellular life-span or even induces immortalization. Consistent with its functional activity, telomerase is silent in most human normal somatic cells while active only in germ-line, stem and other highly proliferative cells. In contrast, telomerase activation widely occurs in human cancer and the enzymatic activity is detectable in up to 90% of malignancies. Recently, hotspot point mutations in the regulatory region of the telomerase reverse transcriptase (TERT) gene, encoding the core catalytic component of telomerase, was identified as a novel mechanism to activate telomerase in cancer. This review discusses the cancer-specific TERT promoter mutations and potential biological and clinical significances.
Highlights
Telomerase is a RNA-dependent DNA polymerase lengthening telomeric DNA (TTAGGG repeats) at the termini of chromosomes [1,2]
We found that the presence of telomerase reverse transcriptase (TERT) promoter mutations was significantly associated with metastases in thyroid and renal pelvic carcinomas [136]
We [93,99] analyzed the effects of TERT promoter mutations, BRAFV600E and age on survival of patients with thyroid cancer, and our results showed that the TERT
Summary
Telomerase is a RNA-dependent DNA polymerase lengthening telomeric DNA (TTAGGG repeats) at the termini of chromosomes [1,2]. Most normal human somatic cells lack telomerase activity due to the tight transcriptional repression of its rate-limiting, catalytic component telomerase reverse transcriptase (hTERT) gene [1,2,3]. Telomere erosion-mediated cellular senescence confers normal cells a limited life-span. Infinite proliferation is a hallmark of malignant cells [1,2]. Overcoming senescence barrier by telomere stabilization is required to acquire infinite cell proliferation potential in oncogenesis, and, in most cases, this is achieved by transcriptional induction of TERT expression accompanied by telomerase activation [1,2]. TERT expression and telomerase activity is widespread and detectable in the majority (up to 90%) of human malignancies [1,2,4]. We discuss these new findings and biological, clinical implications of TERT promoter mutations in human malignancies
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