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Telomerase RNA biogenesis involves sequential binding by Sm and Lsm complexes



In most eukaryotes, the progressive loss of chromosome-terminal DNA sequences is counteracted by the enzyme telomerase, a reverse transcriptase that uses part of an RNA subunit as template to synthesize telomeric repeats. Many cancer cells express high telomerase activity, and mutations in telomerase subunits are associated with degenerative syndromes including dyskeratosis congenita and aplastic anaemia. The therapeutic value of altering telomerase activity thus provides ample impetus to study the biogenesis and regulation of this enzyme in human cells and model systems. We have previously identified a precursor of the fission yeast telomerase RNA subunit (TER1)1 and demonstrated that the mature 3′-end is generated by the spliceosome in a single cleavage reaction akin to the first step of splicing2. Directly upstream and partly overlapping with the spliceosomal cleavage site is a putative binding site for Sm proteins. Sm and like-Sm (LSm) proteins belong to an ancient family of RNA-binding proteins represented in all three domains of life3. Members of this family form ring complexes on specific sets of target RNAs and have critical roles in their biogenesis, function and turnover. Here we demonstrate that the canonical Sm ring and the Lsm2–8 complex sequentially associate with fission yeast TER1. The Sm ring binds to the TER1 precursor, stimulates spliceosomal cleavage and promotes the hypermethylation of the 5′-cap by Tgs1. Sm proteins are then replaced by the Lsm2–8 complex, which promotes the association with the catalytic subunit and protects the mature 3′-end of TER1 from exonucleolytic degradation. Our findings define the sequence of events that occur during telomerase biogenesis and characterize roles for Sm and Lsm complexes as well as for the methylase Tgs1.

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Figure 1: TER1 RNA associates with Sm and Lsm proteins.
Figure 2: Sm proteins associate with TER1 precursor and promote spliceosomal cleavage.
Figure 3: Tgs1 modifies TER1 and is required for normal telomere maintenance.
Figure 4: Lsm proteins replace Sm and protect the 3′-end of TER1.
Figure 5: Lsm binding to TER1 promotes telomerase assembly and protects TER1 from degradation.

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We thank S. Shuman for the tgs1Δ strain, J. A. Box, J. T. Bunch, S. Hartnett and R. M. Helston for technical assistance, the Molecular Biology Core Facility for site-directed mutagenesis and sequencing, D. P. Baumann and R. M. Helston for proofreading the manuscript, and all members of the Baumann laboratory for discussions. This work was funded in part by the Stowers Institute for Medical Research. R.K. is supported by an award from the American Heart Association, and P.B. is an Early Career Scientist with the Howard Hughes Medical Institute.

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Authors and Affiliations



P.B. and W.T. conceived the study and designed the experiments; W.T. performed most of the experiments with some assistance from those acknowledged and P.B.; R.K. contributed to the characterization of Sm mutants and analysed telomere length of Myc-tagged strains. M.B. wrote the script for sequence data analysis and provided advice; W.T., R.K. and P.B. analysed the data, and W.T. and P.B. wrote the manuscript.

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Correspondence to Peter Baumann.

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Tang, W., Kannan, R., Blanchette, M. et al. Telomerase RNA biogenesis involves sequential binding by Sm and Lsm complexes. Nature 484, 260–264 (2012).

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