Abstract
The regulation of telomere length in mammals is crucial for chromosome end-capping and thus for maintaining genome stability and cellular lifespan. This process requires coordination between telomeric protein complexes and the ribonucleoprotein telomerase, which extends the telomeric DNA. Telomeric proteins modulate telomere architecture, recruit telomerase to accessible telomeres and orchestrate the conversion of the newly synthesized telomeric single-stranded DNA tail into double-stranded DNA. Dysfunctional telomere maintenance leads to telomere shortening, which causes human diseases including bone marrow failure, premature ageing and cancer. Recent studies provide new insights into telomerase-related interactions (the ‘telomere replisome’) and reveal new challenges for future telomere structural biology endeavours owing to the dynamic nature of telomere architecture and the great number of structures that telomeres form. In this Review, we discuss recently determined structures of the shelterin and CTC1–STN1–TEN1 (CST) complexes, how they may participate in the regulation of telomere replication and chromosome end-capping, and how disease-causing mutations in their encoding genes may affect specific functions. Major outstanding questions in the field include how all of the telomere components assemble relative to each other and how the switching between different telomere structures is achieved.
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Change history
19 February 2021
A Correction to this paper has been published: https://doi.org/10.1038/s41580-021-00353-x
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Acknowledgements
The authors thank T. de Lange for helpful comments and suggestions. C.L. thanks the members of the Cech laboratory for their support and advice during his postdoctoral years at the University of Colorado Boulder. This work was funded in part by the National Institutes of Health (NIH; R00GM131023) and the Steenbock Career Award from the University of Wisconsin-Madison to C.L. T.R.C. is an investigator at the Howard Hughes Medical Institute.
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T.R.C. is on the board of directors of Merck and a consultant for STORM Therapeutics and Eikon Therapeutics.
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Related links
Human Gene Mutation Database: http://www.hgmd.cf.ac.uk/
Telomerase Database: http://telomerase.asu.edu
Glossary
- G-overhang
-
A telomeric single-stranded DNA 3′ tail consisting of TTAGGG repeats, which is the substrate of telomerase.
- Telomerase
-
A ribonucleoprotein that uses its RNA as a template to synthesize TTAGGG repeats, thereby extending telomeres.
- Processive
-
The ability of an enzyme to perform multiple catalytic reactions without releasing its substrate.
- Telomeric repeat-containing RNA
-
(TERRA). A long non-coding RNA involved in regulating telomerase activity at telomeres.
- Holliday junction
-
A branched DNA structure comprising four double-stranded arms.
- TEL patch
-
(TPP1 glutamate (E) and leucine (L)-rich patch). A small group of amino acids on the surface of the shelterin protein TPP1. The TEL patch directly recruits telomerase to telomeres and then stimulates its activity.
- G-quadruplexes
-
(G4s). Tertiary structures in which groups of four guanines in single-stranded DNA form tetrads through hydrogen bonds.
- Replication protein A
-
(RPA). A eukaryotic single-stranded DNA-binding protein complex involved in DNA replication and repair.
- Telomeric C-strand
-
The telomeric DNA strand consisting of CCCTAA repeats, which pair with the telomerase-synthesized TTAGGG repeats.
- Replisome
-
A multisubunit protein complex that carries out replication of DNA.
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Lim, C.J., Cech, T.R. Shaping human telomeres: from shelterin and CST complexes to telomeric chromatin organization. Nat Rev Mol Cell Biol 22, 283–298 (2021). https://doi.org/10.1038/s41580-021-00328-y
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DOI: https://doi.org/10.1038/s41580-021-00328-y
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