Abstract
Telomerase is a special reverse transcriptase ribonucleoprotein dedicated to the synthesis of telomere repeats that protect chromosome ends. Among reverse transcriptases, telomerase is unique in using a stably associated RNA with an embedded template to synthesize a specified sequence. Moreover, it is capable of iteratively copying the same template region (repeat addition processivity) through multiple rounds of RNA–DNA unpairing and reannealing, that is, the translocation reaction. Biochemical analyses of telomerase over the past 3 decades in protozoa, fungi and mammals have identified structural elements that underpin telomerase mechanisms and have led to models that account for the special attributes of telomerase. Notably, these findings and models can now be interpreted and adjudicated through recent cryo-EM structures of Tetrahymena and human telomerase holoenzyme complexes in association with substrates and regulatory proteins. Collectively, these structures reveal the intricate protein–nucleic acid interactions that potentiate telomerase’s unique translocation reaction and clarify how this enzyme reconfigures the basic reverse transcriptase scaffold to craft a polymerase dedicated to the synthesis of telomere DNA. Among the many new insights is the resolution of the telomerase ‘anchor site’ proposed more than 3 decades ago. The structures also highlight the nearly universal conservation of a protein–protein interface between an oligonucleotide/oligosaccharide-binding (OB)-fold regulatory protein and the telomerase catalytic subunit, which enables spatial and temporal regulation of telomerase function in vivo. In this Review, we discuss key features of the structures in combination with relevant functional analyses. We also examine conserved and divergent aspects of telomerase mechanisms as gleaned from studies in different model organisms.
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The data generated and/or analyzed during the current study are included within the paper and its Supplementary Information or are available from the corresponding author upon reasonable request.
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Acknowledgements
We apologize to our colleagues whose works are not cited due to space constraints. We thank J. Feigon and K. Nguyen for insightful comments on the manuscript, and we thank A. Young for discussion and helpful suggestions. Work in our laboratories is supported by the Canadian Institutes of Health Research (grant PJT-166130) and a Natural Sciences and Engineering Research Council of Canada Discovery grant (C.A.) and by NSF MCB-1817331, NIH GM107287 and Hearst Endowed Faculty Fellow Fund (N.F.L.).
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Lue, N.F., Autexier, C. Orchestrating nucleic acid–protein interactions at chromosome ends: telomerase mechanisms come into focus. Nat Struct Mol Biol 30, 878–890 (2023). https://doi.org/10.1038/s41594-023-01022-7
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DOI: https://doi.org/10.1038/s41594-023-01022-7