title: The major reverse transcriptase-incompetent splice variant of the human telomerase protein inhibits telomerase activity but protects from apoptosis.
abstract: Human telomerase reverse transcriptase (hTERT; the catalytic protein subunit of telomerase) is subjected to numerous alternative splicing events, but the regulation and function of these splice variants is obscure. Full-length hTERT includes conserved domains that encode reverse transcriptase activity, RNA binding, and other functions. The major splice variant termed α+β- or β-deletion is highly expressed in stem and cancer cells, where it codes for a truncated protein lacking most of the reverse transcriptase domain but retaining the known RNA-binding motifs. In a breast cancer cell panel, we found that β-deletion was the hTERT transcript that was most highly expressed. Splicing of this transcript was controlled by the splice regulators SRSF11, HNRNPH2, and HNRNPL, and the β-deletion transcript variant was associated with polyribosomes in cells. When ectopically overexpressed, β-deletion protein competed for binding to telomerase RNA (hTR/TERC), thereby inhibiting endogenous telomerase activity. Overexpressed β-deletion protein localized to the nucleus and mitochondria and protected breast cancer cells from cisplatin-induced apoptosis. Our results reveal that a major hTERT splice variant can confer a growth advantage to cancer cells independent of telomere maintenance, suggesting that hTERT makes multiple contributions to cancer pathophysiology.
authors.affiliation: Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, California, USA.
authors.forename: Imke
authors.initials: I
authors.lastname: Listerman
authors.forename: Jie
authors.initials: J
authors.lastname: Sun
authors.forename: Francesca S
authors.initials: FS
authors.lastname: Gazzaniga
authors.forename: Jason L
authors.initials: JL
authors.lastname: Lukas
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Blackburn
mesh_terms: D017398:Alternative Splicing; D017209:Apoptosis; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology; D017353:Gene Deletion; D017930:Genes, Reporter; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D019169:Jurkat Cells; D008928:Mitochondria / Q000378:metabolism; D011485:Protein Binding; D012313:RNA / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism; D019098:Telomerase / Q000235:genetics*
chemical_list: D007527:Isoenzymes; D012313:RNA; D019098:Telomerase; D002945:Cisplatin