hTERT: another brick in the wall against DNA damage and cancer.

In human cancer, expression of telomerase is positively correlated with prognosis, tumour aggressiveness, and metastatic potential. There is accumulating evidence that hTERT (the catalytic subunit of telomerase with reverse transcriptase activity) favours an immortal phenotype by blocking programmed cell death (apoptosis) independently of its protective function at the telomere ends. This review summarized existing evidence for the anti-apoptotic role of hTERT in the context of tumour-cell resistance against DNA damage and aims to put hTERT in the context of cell-signal-transduction pathways leading either to survival or cell death. We found evidence that telomerase is cross-linked with many different signaling pathways that regulate cell proliferation, DNA damage repair, and also cell death. Thereby, hTERT survival function seems to occur at early stages of DNA damage recognition. We found some discrepancies in the published data, and it remains unclear whether apoptosis induction via hTERT abrogation occurs via acute telomere loss because telomere-length assessment was not included in study designs. Based on our findings, we suggest further exploration is needed of the interplay of the DNA damage response signaling network, including MAPK and p53 family activation, on telomerase regulation because this interaction is probably an important factor for fine tuning of the sensitivity of the cell to genotoxic stress. Using anti-neoplastic agents, further dose relationships on timing and extent of DNA damage, cellular repair, and death should be established and correlated with hTERT expression/telomerase activation. Closing the data gaps identified here could profoundly improve our understanding of the relevance of telomerase for protecting the cell against anti-cancer agents and would contribute to developing new strategies for cancer therapy.
Copyright © 2012. Published by Elsevier B.V.
PMID: 23287739