Abstract
Telomeres maintain genomic integrity in normal cells, and their progressive shortening during successive cell divisions induces chromosomal instability. In the large majority of cancer cells, telomere length is maintained by telomerase. Thus, telomere length and telomerase activity are crucial for cancer initiation and the survival of tumors. Several pathways that regulate telomere length have been identified, and genome-scale studies have helped in mapping genes that are involved in telomere length control. Additionally, genomic screening for recurrent human telomerase gene hTERT promoter mutations and mutations in genes involved in the alternative lengthening of telomeres pathway, such as ATRX and DAXX, has elucidated how these genomic changes contribute to the activation of telomere maintenance mechanisms in cancer cells. Attempts have also been made to develop telomere length- and telomerase-based diagnostic tools and anticancer therapeutics. Recent efforts have revealed key aspects of telomerase assembly, intracellular trafficking and recruitment to telomeres for completing DNA synthesis, which may provide novel targets for the development of anticancer agents. Here, we summarize telomere organization and function and its role in oncogenesis. We also highlight genomic mutations that lead to reactivation of telomerase, and mechanisms of telomerase reconstitution and trafficking that shed light on its function in cancer initiation and tumor development. Additionally, recent advances in the clinical development of telomerase inhibitors, as well as potential novel targets, will be summarized.
Highlights
Cancer is generally an age-related genetic disease, manifesting only when normal cells accumulate genomic instability over a period of time and acquire the capability of replicative immortality
While human telomerase reverse transcriptase (TERT) gene (hTERT) promoter mutations are frequent in multiple non-epithelial cancer types and their distribution is similar in the majority of patients, Chiba and coworkers [49] have emphasized that the impact of hTERT promoter mutations has mostly been studied in already transformed immortal tumor cells with active telomerase maintaining their telomeres
Conclusions and future perspectives Telomere maintenance has been extensively studied, and our understanding of the role of telomerase and alternative lengthening of telomeres (ALT) in cancer has improved remarkably in recent years. It is becoming clear how cancer cells regulate different molecular events involved in telomere maintenance to expand their proliferative capacity
Summary
Cancer is generally an age-related genetic disease, manifesting only when normal cells accumulate genomic instability over a period of time and acquire the capability of replicative immortality. Studies using telomerase inhibition strategies have established that robust hTERT inhibition can lead to progressive telomere shortening and eventually cancer cell death.
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