Alternative splicing regulation of telomerase: a new paradigm?

• Regulation of alternative splicing in abundant housekeeping genes is well studied.
• Low-abundance gene regulation, including splicing, is understudied but may play key roles in cancer.
• TERT, a low-abundance transcript, is alternatively spliced via unique regulatory mechanisms.
• Understanding TERT splicing may provide new cancer therapy approaches.

Alternative splicing affects approximately 95% of eukaryotic genes, greatly expanding the coding capacity of complex genomes. Although our understanding of alternative splicing has increased rapidly, current knowledge of splicing regulation has largely been derived from studies of highly expressed mRNAs. Telomerase is a key example of a protein that is alternatively spliced, but it is expressed at very low levels and although it is known that misregulation of telomerase splicing is a hallmark of nearly all cancers, the details of this process are unclear. Here we review work showing that hTERT expression is in part regulated by atypical alternative splicing, perhaps due to its exceptionally low expression level. We propose that these differential regulatory mechanisms may be widely applicable to other genes and may provide new opportunities for the development of cancer therapeutics.