Abstract
Telomerase adds telomeric repeats onto chromosome ends and is almost universally upregulated in human cancers. Here we demonstrate that RNA:RNA pairing regulates splicing of the catalytic subunit of human telomerase (TERT). Human alleles contain a variable number of 38 bp repeats within TERT intron 6 (>1 kb from exon–intron junctions). At least nine repeats are required for generating the major non-functional ‘minus beta’ isoform, which skips exons 7 and 8. RNA:RNA pairing between the repeats and the pre-mRNA might bring exons 6 and 9 closer, thereby promoting exon skipping. To demonstrate this, we show that mutations within the repeat that abolish exon skipping are corrected by compensatory mutations in the pre-mRNA. This study thus identifies RNA:RNA pairing by repetitive sequences as a novel form of alternative splicing regulation in a gene crucial for cancer survival and sheds new light on functional roles for short repetitive sequences embedded deep within introns throughout the genome.
Highlights
Telomerase adds telomeric repeats onto chromosome ends and is almost universally upregulated in human cancers
We have identified a region within intron 6 of hTERT pre-mRNA that contains a variable number of bp repeats, that lies 41 kb from exon–intron junctions, and is only conserved in old but not new world primates or other mammals
We show that a block of repeats promotes exon skipping through RNA:RNA pairing between the repeat sequences and the distal portion of the TERT pre-mRNA
Summary
Telomerase adds telomeric repeats onto chromosome ends and is almost universally upregulated in human cancers. We demonstrate that RNA:RNA pairing regulates splicing of the catalytic subunit of human telomerase (TERT). Introduction of the catalytic subunit of telomerase (TERT) into normal cells prevents replicative senescence, an initial barrier to the accumulation of mutations as part of cancer initiation and progression[8,9]. (a) Splicing of TERT pre-mRNA (not to scale) without the block of repeats in intron 6 results in exclusively full-length splicing, where all exons are included in the final transcript. (b) Splicing of TERT pre-mRNA in the presence of the block of repeats in intron 6 produces both the full-length transcript and an alternatively splice transcript called minus beta as a result of the skipping of exons 7 and 8. The minus beta splice form is non-functional because exons 7 and 8 are in the reverse transcriptase domain and required for telomerase activity
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