Tissue‐specific alternate splicing of human telomerase reverse transcriptase (hTERT) influences telomere lengths during human development

Abstract

Direct genetic manipulations have shown that telomerasemediated telomere elongation plays a key role in determining cellular replicative capacity and senescence. The mechanisms regulating the production of an active telomerase enzyme are still predominantly unknown, although roles for transcriptional control of hTERT, alternative-splicing of hTERT transcripts, and post-translational phosphorylation of hTERT protein have been advocated. Here we show that hTERT is alternatively spliced in specific patterns by different tissue types during human development. Alternative splicing often prohibits the expression of hTERT protein containing functional reverse transcriptase domains. In these instances, telomerase activity is absent, leading to shortening of telomeres. The specific pattern of hTERT mRNA variants in human development provides evidence that alternative splicing is non-random and participates in the regulation of telomerase activity.

Quantitative relationship between functionally active telomerase and major telomerase components (hTERT and hTR) in acute leukaemia cells

“…Alternative splicing machinery of hTERT is considered to be tissue specific and to influence telomere lengths during human development (Ulaner et al, 2001). It has been shown that hTERT RNA alternative splicing mediates telomerase downregulation induced by the G-quadruplex ligand 12459 (Gomez et al, 2004).…”

Telomerase in the human organism

“…These assays examine the aggregate of numerous cell types present in whole tissue samples, including migrating or circulating cells present at the time of the assay (for example, fetal spleen and liver are sites of hematopoiesis). However, some correlation can be made between telomerase inactivation, di erentiation and increased rate of telomere loss with time (Ulaner and Giudice, 1997;Ulaner et al, 2001). In heart tissue, loss of activity occurs concomitant with loss of TERT mRNA expression; loss of activity in kidney instead occurs concomitant with a change in the pattern of TERT pre-mRNA splicing (Ulaner et al, 1998).…”

Telomerase catalytic subunit in laryngeal carcinogenesis—an immunohistochemical study

“…5 Several splice variants of the hTERT gene transcript have been described. 9,10 However, it is generally accepted that only the full-length transcript of the hTERT gene can function as the catalytic subunit of telomerase, since it contains the whole core catalytic domain and the specialised carboxy-terminus of this transcriptase. 11 We have recently demonstrated that telomerase catalytic subunit (hTERT) mRNA relative quantities increase progressively with the degree of laryngeal epithelial abnormalities by using RT-PCR, and hypothesised that hTERT gene re-expression represents an early event in the multistep process of laryngeal carcinogenesis.…”