The spliceosome is best known for shepherding primary messenger RNA transcripts to maturity. This enzyme complex also contributes to the synthesis of an enzyme that maintains chromosome ends.
When the Stargate Atlantis Expedition Team found Dr Beckett at a distant galactic outpost, they figured that he was a clone of the late Dr Beckett because his telomeres were 30% shorter than expected for his age1. That the complex concept of telomere dynamics has permeated popular fiction testifies to their significance. These repetitive DNA sequences are known to have key roles in fundamental processes such as ageing, tissue renewal, cell proliferation and cancer2. Nonetheless, many aspects of telomere synthesis and processing remain elusive. On page 910 of this issue, Box et al.3 report the unexpected finding that, at least in a yeast species, telomere synthesis and maintenance depend on the incomplete activity of a molecular machine called the spliceosome, which normally functions in generating mature messenger RNA from the longer primary gene transcripts.
Telomeres protect the ends of chromosomes both from the continuous shrinkage associated with the mechanism of DNA replication, and from being recognized as DNA breaks, which are susceptible to genomic rearrangements. A remarkable enzyme complex known as telomerase maintains and controls telomere length4. One component of this molecule is a cellular reverse transcriptase enzyme, which uses another component — an RNA template known as the telomerase RNA — to add telomeric repeats to chromosome ends (Fig. 1a). Previous work in the fission yeast Schizosaccharomyces pombe identified ter1 as the gene encoding telomerase RNA, and demonstrated the existence of transcripts longer than the functional telomerase RNA, which is present in the telomerase enzyme complex5,6. The function of these longer transcripts, which, like mRNAs, carry a sequence of adenine nucleotides called a polyadenylate tail, remained unknown.
In eukaryotes (organisms such as yeast, plants and animals), the spliceosome processes primary RNA transcripts to mature mRNAs that can be translated into proteins7. This process involves the removal of sequences that don't encode proteins (introns) and the splicing together of those that do (exons). Box et al.3 realized that some of the longer polyadenylated telomerase-RNA transcripts in S. pombe differ from their shorter, functional counterpart in having an intron that harbours putative splicing signals at its ends; this observation hinted at a role for the spliceosome in the processing of telomerase RNA.
Indeed, the authors find that mutation of the splicing signals greatly reduced the levels of the shorter telomerase RNA, and consequently compromised telomerase function, leading to telomere shortening. Box et al. therefore conclude that splicing of the longer, polyadenylated transcripts is necessary for generating functional telomerase RNA and for telomerase activity. They propose that the longer transcripts act as precursors, which are converted by the spliceosome to functional telomerase RNA.
Normally, the spliceosome removes an intron in two consecutive reactions. First, it cleaves the intron's 5′ end, allowing the free 5′ phosphate to form a phosphodiester bond with an adenosine nucleotide — known as the branch site — located close to the intron's 3′ end (Fig. 1b). Next, the intron is cleaved at its 3′ end, and the exons are spliced together. Box and colleagues find that the 3′ end of functional telomerase RNA precisely coincides with the 5′ boundary of the intron present in the longer transcripts. So it seems that the site-specific cleavage activity of the spliceosome during the first step of the reaction generates the proper 3′ end of telomerase RNA.
As essential as the cleavage of the telomerase RNA precursor is, it is equally important that the spliceosome is prevented from completing its normal function of splicing the exons together, because this would lead to a different 3′ end for the mature telomerase RNA and so a non-functional molecule (Fig. 1b). Box et al. demonstrate that an unusually long distance between the branch site and the 3′ end of the intron prevents efficient completion of the second step, and that this arrangement allows accumulation of what would normally be reaction intermediates. In the case of telomerase RNA, however, one of these intermediates is the final, processed product that functions as part of the telomerase enzyme. It is therefore the incomplete function of the spliceosome — as measured by mRNA-production standards — that is needed for the formation of telomerase RNA.
Telomerase activity is essential for long-term cell proliferation — including stem-cell renewal and cancer-cell immortalization — and increased telomerase activity can delay ageing in cancer-resistant mice2,8. So it will be of interest to know whether Box and colleagues' results3 in S. pombe apply to other organisms.
Conceivably, modulation of spliceosome activity — such as changes in the efficiency of the second catalytic step and of the release of splicing intermediates from the spliceosome complex — could control telomerase function in organisms in which telomerase RNA follows this processing route. Polyadenylated and/or longer telomerase-gene transcripts have been identified in other species, including humans9,10, but whether the spliceosome plays a part in the synthesis of telomeric RNA in these organisms remains unknown.
A notable insight comes from Box and colleagues' observation that the spliceosome can generate the proper 3′ end of telomerase RNA. It could be that other RNA molecules can similarly exploit this incomplete activity of the spliceosome to generate alternative transcript ends. If so, the expanding world of non-coding RNAs, many of which contain introns, could offer a large inventory of substrates for diversification of the cellular pool of RNA transcripts, adding to the complexity of the still largely hidden genetic program of our genomes11.