Extra-Telomeric Effects of Telomerase (hTERT) in Cell Death

Bellot, Gaëtan

doi:10.5772/48583

Cited by 1 publication

(1 citation statement)

References 96 publications

(120 reference statements)

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“…In other words, high cell cycle rates obviously require also high rates of MMR and of TMM to compensate for replication errors and telomere attrition, respectively, which, in turn, relate to increased apoptosis rates (69) that require feedback toward increased cell cycle activity for net survival of the cells. On one hand, TMM, especially TEL, represses apoptosis via telomere maintenance and probably also by extra-telomeric functions of TERT , e.g., via modulation of oxidative stress in mitochondria and interactions with apoptotic pathways [see (70) and references cited therein]. On the other hand, only a part of cells acquires immortality at telomere crisis and proceeds to cancerogenesis while the other part becomes apoptotic (71).…”

Section: Resultsmentioning

confidence: 99%

Telomere Length Maintenance and Its Transcriptional Regulation in Lynch Syndrome and Sporadic Colorectal Carcinoma

et al. 2019

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Background: Activation of telomere maintenance mechanisms (TMMs) is a hallmark of most cancers, and is required to prevent genome instability and to establish cellular immortality through reconstitution of capping of chromosome ends. TMM depends on the cancer type. Comparative studies linking tumor biology and TMM have potential impact for evaluating cancer onset and development.Methods: We have studied alterations of telomere length, their sequence composition and transcriptional regulation in mismatch repair deficient colorectal cancers arising in Lynch syndrome (LS-CRC) and microsatellite instable (MSI) sporadic CRC (MSI s-CRC), and for comparison, in microsatellite stable (MSS) s-CRC and in benign colon mucosa. Our study applied bioinformatics analysis of whole genome DNA and RNA sequencing data and a pathway model to study telomere length alterations and the potential effect of the “classical” telomerase (TEL-) and alternative (ALT-) TMM using transcriptomic signatures.Results: We have found progressive decrease of mean telomere length in all cancer subtypes compared with reference systems. Our results support the view that telomere attrition is an early event in tumorigenesis. TMM gets activated in all tumors studied due to concerted overexpression of a large fraction of genes with direct relation to telomere function, where only a very small fraction of them showed recurrent mutations. TEL-related transcriptional state was dominating in all CRC subtypes, showing, however, subtype-specific activation patterns; while contribution of the ALT-TMM was slightly more prominent in the hypermutated MSI s-CRC and LS-CRC. TEL-TMM is mainly activated by over-expression of DKC1 and/or TERT genes and their interaction partners, where DKC1 is more prominent in MSS than in MSI s-CRC and can serve as a transcriptomic marker of TMM activity.Conclusions: Our results suggest that transcriptional patterns are indicative for TMM pathway activation with subtle differences between TEL and ALT mechanisms in a CRC subtype-specific fashion. Sequencing data potentially provide a suited measure to study alterations of telomere length and of underlying transcriptional regulation. Further studies are needed to improve this method.

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Section: Resultsmentioning

confidence: 99%