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  • Review Article
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Finding the end: recruitment of telomerase to telomeres

Nature Reviews Molecular Cell Biology volume 14, pages 69–82 (2013)Cite this article

Subjects

Key Points

  • The ends of linear chromosomes pose two problems to eukaryotic cells: the end-protection problem; and the end-replication problem. End protection is necessary to prevent natural ends of chromosomes from being recognized as DNA breaks that require DNA repair, and end replication is required to compensate for the inability of replicative polymerases to copy the extreme ends of chromosomes.

  • The telomerase ribonucleoprotein enzyme uses its internal RNA template for replicating the ends of chromosomes to furnish telomeric DNA, which is bound by telomeric proteins that facilitate chromosome end protection.

  • How does telomerase get recruited to chromosomes? The telomerase–telomere connection is mediated by TPP1 in humans, Ccq1 in fission yeast and Cdc13 in budding yeast. The amino-terminal OB-fold domain of human TPP1 binds telomerase, recruits telomerase to telomeres and increases telomerase processivity.

  • Ccq1, a Schizosaccharomyces pombe-specific telomeric protein, recruits telomerase to telomeres in this organism. Phosphorylation of Ccq1 by the Tel1 and Rad3 kinases regulates its binding to the ever shorter telomeres 1 (Est1) subunit of S. pombe telomerase.

  • Binding of the heterodimeric Ku70–Ku80 to its binding site on Tlc1, the RNA subunit of Saccharomyces cerevisiae telomerase, facilitates localization of telomerase in the nucleus of this organism. The interaction between the telomeric single-stranded DNA-binding protein Cdc13 and the telomerase subunit Est1 tethers budding yeast telomerase to telomeres.

Abstract

Telomeres, the ends of linear eukaryotic chromosomes, are characterized by the presence of multiple repeats of a short DNA sequence. This telomeric DNA is protected from illicit repair by telomere-associated proteins, which in mammals form the shelterin complex. Replicative polymerases are unable to synthesize DNA at the extreme ends of chromosomes, but in unicellular eukaryotes such as yeast and in mammalian germ cells and stem cells, telomere length is maintained by a ribonucleoprotein enzyme known as telomerase. Recent work has provided insights into the mechanisms of telomerase recruitment to telomeres, highlighting the contribution of telomere-associated proteins, including TPP1 in humans, Ccq1 in Schizosaccharomyces pombe and Cdc13 and Ku70–Ku80 in Saccharomyces cerevisiae.

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Figure 1: Chromosome end protection versus telomerase recruitment and action.
Figure 2: Structures of telomeric proteins and telomerase components.
Figure 3: Models for telomerase recruitment in humans and S. pombe.
Figure 4: Model for telomerase recruitment in Saccharomyces cerevisiae.

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Acknowledgements

T.R.C. is an investigator at the Howard Hughes Medical Institute. The telomerase research in the author's laboratory is funded in part by the US National Institutes of Health (NIH) grants R01 GM099705 to T.R.C. and K99 CA167644 to J.N.

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  1. Department of Chemistry and Biochemistry, Howard Hughes Medical Institute, BioFrontiers Institute, University of Colorado, Boulder, 80309-0596, Colorado, USA

    Jayakrishnan Nandakumar & Thomas R. Cech

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Thomas R. Cech and Jayakrishnan Nandakumarare inventors on a patent application relating to the identification of a patch on TPP1 that mediates telomerase recruitment.

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Glossary

Dyskeratosis congenita

A rare genetic disease, characterized by abnormal skin pigmentation, nail dystrophy and mucosal leukoplakia, caused by telomere shortening owing to mutations in telomerase core components (telomerase reverse transcriptase (TERT) and a template-containing RNA component (TR)), telomerase accessory factors (such as dyskerin, telomerase Cajal body protein 1 (TCAB1), NHP2 and nucleolar protein 10 (Nop10)), or the shelterin protein TRF1-interacting nuclear protein 2 (TIN2).

Hoogsteen base-pairing

Non-Watson–Crick pairing that involves the N7 atom of a purine and is important in stabilizing triplex and quadruplex nucleic acid structures.

Cajal bodies

Conserved nuclear organelles that are involved in the biogenesis of small nuclear ribonucleoprotein (snRNP) particles and the maturation of the telomerase RNP.

Sm proteins

Proteins that form a ring which binds to a specific U-rich sequence near the 3′ ends of small nuclear RNAs involved in mRNA splicing, allowing nuclear import of the ribonucleoprotein.

T-motif

An amino acid sequence preceding the reverse transcriptase motif that is conserved among telomerase reverse transcriptase (TERT) proteins but not apparent in other reverse transcriptases.

Photocrosslink

The formation of covalent adducts between nucleotides and/or amino acids that are adjacent in a complex using light energy, generally in the ultraviolet range.

Immunofluorescence

Localization of a protein (or other macromolecule) within cells or tissues using a specific antibody that is derivatized with a fluorescent probe (direct immunofluorescence) or using a fluorescently labelled secondary antibody (indirect immunofluorescence).

Fluorescence in situ hybridization

(FISH). Localization of specific nucleic acid sequences in the cell by specific annealing of fluorescently labelled antisense oligonucleotide probes.

Chromatin immunoprecipitation

(ChIP). A technique that allows the isolation of DNA sequences bound to a protein of interest using specific antibodies.

Non-homologous end-joining

(NHEJ). A repair pathway of DNA double-strand breaks by directly ligating the broken ends without the need for a homologous template.

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Nandakumar, J., Cech, T. Finding the end: recruitment of telomerase to telomeres. Nat Rev Mol Cell Biol 14, 69–82 (2013). https://doi.org/10.1038/nrm3505

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