While studying telomere end protection, we found that some point mutations in Pot1 cause dramatic telomere lengthening, indicative of a role for Pot1 in regulating telomerase. Subsequent studies showed tha
t the amount of telomere-bound Pot1 is tightly controlled to allow limited access by telomerase while preventing catastrophic loss of telomeres (Bunch et al., 2005). The realization that Pot1 functions in regulating telomerase has heightened our interest in this fascinating enzyme. Although the core components of human telomerase have been known for some time, our understanding of telomerase assembly, function and regulation has remained limited. Given the key role of this enzyme in cancer and senescence, it seems a highly worthwhile endeavor to thoroughly investigate this ribonucleoprotein complex with the long-term goal of developing compounds that can modulate telomerase activity in vivo.
Until recently, the fission yeast S. pombe was of limited use in studying telomerase as the gene that encodes the telomerase RNA subunit had not been identified. We have recently affinity-purified telomerase, cloned the RNA subunit (TER1) and started the characterization of functional elements (Leonardi et al., 2008). As part of this analysis we established a precursor-product relationship between longer poly-adenylated forms and the mature 3’ end of TER1 found in complex with the catalytic subunit of telomerase. As telomerase RNA processing is only poorly understood in any organism, we designed a series of experiments to examine how the precursors are trimmed to the mature length. These studies led us to the highly unexpected realization that the spliceosome has a novel function in 3’ end processing of this non-coding RNA (Box, Bunch et al., 2008). Instead of removing an intronic sequence in a two-step process, the first transesterification reaction alone generates the mature 3’ end of TER1 (Figure 1). We refer to this process as slicing to distinguish it from splicing yet acknowledge the mechanistic similarities.
Naturally, we are very intrigued by these observations and we are in the process of characterizing the mechanism of slicing, its regulation and a comprehensive set of substrates.