The major reverse transcriptase-incompetent splice variant of the human telomerase protein inhibits telomerase activity but protects from apoptosis

Cancer Res. 2013 May 1;73(9):2817-28. doi: 10.1158/0008-5472.CAN-12-3082. Epub 2013 Apr 22.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing*
  • Apoptosis*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology*
  • Cell Nucleus / metabolism
  • Cell Proliferation
  • Cisplatin / pharmacology
  • Gene Deletion
  • Genes, Reporter
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Isoenzymes / genetics
  • Jurkat Cells
  • Mitochondria / metabolism
  • Protein Binding
  • RNA / metabolism
  • Ribosomes / metabolism
  • Telomerase / genetics*

Substances

  • Isoenzymes
  • RNA
  • Telomerase
  • Cisplatin