Regulation of Telomerase Alternative Splicing: A Target for Chemotherapy

SummaryTelomerase is present in human cancer cells but absent in most somatic tissues. The messenger RNA of human telomerase (hTERT) is alternatively spliced into mostly nonfunctional products. We sought to understand splicing so that we could decrease functional splice isoforms to reduce telomerase activity in order to complement direct enzyme inhibition. Unexpectedly, minigenes containing hTERT exons 5–10 flanked by 150–300 bp intronic sequences did not produce alternative splicing. A 1.1 kb region of 38 bp repeats ∼2 kb from the exon 6/intron junction restored the exclusion of exons 7 and 8. An element within intron 8, also >1 kb from intron/exon junctions, modulated this effect. Transducing an oligonucleotide complementary to this second element increased nonfunctional hTERT messenger RNA from endogenous telomerase. These results demonstrate the potential of manipulating hTERT splicing for both chemotherapy and regenerative medicine and provide specific sequences deep within introns that regulate alternative splicing in mammalian cells by mechanisms other than the introduction of cryptic splice sites.

Graphical AbstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Alternative splicing is a new target for telomerase inhibition/activation ► Elements deep within introns regulate human telomerase splicing ► These intronic elements contain both unusual short repeats and direct repeats ► A direct-repeat oligonucleotide modifies splicing of endogenous telomerase