The Role of Alternative RNA Splicing in the Regulation ofhTERT, Telomerase, and Telomeres: Implications for Cancer Therapeutics

Alternative RNA splicing impacts the majority (>90%) of eukaryotic multi-exon genes, expanding the coding capacity and regulating the abundance of gene isoforms. Telomerase (hTERT) is a key example of a gene that is alternatively spliced during human fetal development and becomes dysregulated in nearly all cancers. Approximately 90% of human tumors use telomerase to synthesizede novotelomere repeats and obtain telomere-dependent cellular immortality. Paradigm shifting data indicates thathTERTalternative splicing, in addition to transcription, plays an important role in the regulation of active telomerase in cells. Our group and others are pursuing the basic science studies to progress this emerging area of telomerase biology. Recent evidence demonstrates that switching splicing ofhTERTfrom the telomerase activity producing full-lengthhTERTisoform to alternatively spliced, non-coding isoforms may be a novel telomerase inhibition strategy to prevent cancer growth and survival. Thus, the goals of this review are to detail the general roles of telomerase in cancer development, explore the emerging regulatory mechanisms of alternative RNA splicing of thehTERTgene in various somatic and cancer cell types, define the known and potential roles ofhTERTsplice isoforms in cancer cell biology, and provide insight into new treatment strategies targetinghTERTin telomerase-positive cancers.