title: The hTERTalpha splice variant is a dominant negative inhibitor of telomerase activity.
abstract: The telomerase catalytic subunit (hTERT) is an essential component of the holoenzyme complex that adds telomeric repeats to the ends of human chromosomes. Maintenance of telomeres by telomerase or another mechanism is required for cell immortalization, and loss of telomeric DNA has been proposed as a trigger for cellular senescence. Available evidence suggests that regulation of telomerase activity primarily depends on transcriptional control of hTERT. However, several human tissues as well as some normal cell strains have been shown to express low levels of hTERT mRNA even though they lack telomerase activity. We have previously identified six splice variants of hTERT, including a "deletion" variant (hTERTalpha) that is missing conserved residues from the catalytic core of the protein. Several of the deletion variants have been detected in normal and developing human tissues. We now show that hTERTalpha inhibits endogenous telomerase activity, which results in telomere shortening and chromosome end-to-end fusions. Telomerase inhibition induced a senescence-like state in HT1080 cells and apoptosis in a jejunal fibroblast cell line. These results suggest a possible role for hTERT splice variants in the regulation of telomerase activity.
authors.affiliation: Children's Medical Research Institute, Westmead, New South Wales, Australia.
authors.forename: L M
authors.initials: LM
authors.lastname: Colgin
authors.forename: C
authors.initials: C
authors.lastname: Wilkinson
authors.forename: A
authors.initials: A
authors.lastname: Englezou
authors.forename: A
authors.initials: A
authors.lastname: Kilian
authors.forename: M O
authors.initials: MO
authors.lastname: Robinson
authors.forename: R R
authors.initials: RR
authors.lastname: Reddel
mesh_terms: D017398:Alternative Splicing; D017209:Apoptosis; D002384:Catalysis; D020134:Catalytic Domain; D002461:Cell Line, Transformed / Q000201:enzymology; D016922:Cellular Senescence; D002869:Chromosome Aberrations; D002877:Chromosomes, Human / Q000648:ultrastructure; D004268:DNA-Binding Proteins; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D005799:Genes, Dominant; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007583:Jejunum / Q000166:cytology; D017354:Point Mutation; D021122:Protein Subunits; D012313:RNA; D012333:RNA, Messenger / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000502:physiology; D017384:Sequence Deletion; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D016615:Telomere / Q000378:metabolism / Q000648:ultrastructure; D014162:Transfection
chemical_list: D004268:DNA-Binding Proteins; D021122:Protein Subunits; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase