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The biogenesis and regulation of telomerase holoenzymes

Key Points

  • Telomerase is an essential eukaryotic reverse transcriptase that is devoted to balancing the net length of the telomeric repeat tracts at chromosome ends. Telomerase is distinct as a polymerase in its dependence on integral protein and RNA subunits, both of which establish the biochemical properties of enzyme activity.

  • Telomerase ribonucleoproteins are endogenously assembled in step-wise pathways under the direction of chaperones. Ribonucleoprotein stability requires species-specific RNA-binding proteins that fold, protect and traffic the telomerase RNA.

  • Telomerase activity at chromosome ends is dependent on proteins that join the stable telomerase ribonucleoprotein to form a catalytically active and telomere-enabled telomerase holoenzyme. How telomerase-associated proteins and structural changes in telomeric chromatin cooperate to determine the extent of repeat synthesis is an interesting open question.

  • The assembly and regulation of telomerase holoenzymes seems to be highly dynamic. Changes in the subcellular distribution of enzyme subunits, their assembly and their access to DNA occur across the cell cycle and also vary with cell type. Numerous known and unknown associated proteins are likely to modulate telomerase assembly and regulation in vivo, and their identification could provide insights into the physiological significance of telomerase dynamics.

  • To accomplish accurate and efficient telomeric repeat synthesis, protein–RNA, protein–DNA and RNA–DNA interactions must be coordinated through the progression of a multi-step telomerase catalytic cycle. Insights into telomerase structure and mechanism are just beginning to provide a picture of the complex engineering that governs template and substrate access to the active site.

Abstract

Chromosome stability requires a dynamic balance of DNA loss and gain in each terminal tract of telomeric repeats. Repeat addition by a specialized reverse transcriptase, telomerase, has an important role in maintaining this equilibrium. Insights that have been gained into the cellular pathways for biogenesis and regulation of telomerase ribonucleoproteins raise new questions, particularly concerning the dynamic nature of this unique polymerase.

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Figure 1: Endogenous biogenesis pathways for telomerase holoenzymes.
Figure 2: Regulated engagement of telomerase with its chromosome substrates.
Figure 3: A multi-step catalytic cycle for telomeric repeat synthesis.
Figure 4: Working model for TERT domain architecture.

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Acknowledgements

I apologize to authors whose work could not be described thoroughly within the text and reference limits. Research in the Collins laboratory has been supported by the National Institutes of Health, Burroughs Wellcome Fund, American Cancer Society and the UC Cancer Research Coordinating Committee. I thank the members of the Collins laboratory over the past decade for creating such a stimulating and supportive research environment. I also thank T. Cech and C. O'Connor for their comments on the original draft of this review.

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Glossary

Telomere

The terminal domain of an intact chromosome that protects DNA termini from inappropriate degradation, recombination or fusion with other chromosome ends.

Ciliates

Large single-celled eukaryotes that differentiate both the germline and the somatic versions of their nucleus within a common cytosol.

CCA-adding enzyme

The enzyme that adds or repairs the CCA-3′ end that is shared by all functional transfer RNAs and that catalyses distinct, successive, sequence-specific nucleotide-transfer reactions.

RNase P

An RNP with an ancestral catalytic RNA that performs a phosphodiester cleavage reaction to generate the mature 5′ end of transfer RNAs.

Small nuclear (sn) RNP

Non-coding snRNA assembles as an sn ribonucleoprotein (snRNP), which typically functions in the nucleus in RNA processing.

H/ACA motif

An RNA motif with a consensus structure that includes, from 5′ to 3′ with conserved spacing, a hairpin stem, a hinge sequence, a second hairpin stem and an ACA sequence.

Cajal body

A nuclear compartment that forms in a subset of cell types and contains factors that process, modify and assemble RNPs.

Ku

A heterodimeric protein that forms a basket-like structure for encircling DNA ends and that recruits the DNA-repair machinery to DNA breaks.

Heterogeneous nuclear (hn) RNP proteins

Abundant proteins that were initially identified by their association with bulk nuclear pre-mRNA and are now recognized to have additional more specialized functions.

Nucleolus

A nuclear compartment that forms by coupled transcription, processing and RNP assembly of ribosomal RNAs. It also has roles in sequestration of cell-cycle regulators, transcription factors and other molecules from their sites of action.

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Collins, K. The biogenesis and regulation of telomerase holoenzymes. Nat Rev Mol Cell Biol 7, 484–494 (2006). https://doi.org/10.1038/nrm1961

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