Key Points
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Telomeric proteins control telomere length and telomere integrity. The six bona fide telomeric binding proteins form shelterin, a complex that maintains chromosome end integrity.
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Telomere dysfunction can be caused by loss of telomeric repeats or by loss of protective features, both of which are essential for telomere function.
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Functional telomeres interact with the DNA damage machinery, but the machinery is prevented from processing these ends. Dysfunctional telomeres are recognized as damage and repaired.
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Repair of dysfunctional telomeres by fusion propels cells into breakage–fusion–bridge cycles, resulting in unequal distribution of genetic material into daughter cells and, therefore, genome instability.
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Telomere dysfunction and the failure to maintain telomere length is emerging as being the cause of several diseases.
Abstract
The natural ends of linear chromosomes require unique genetic and structural adaptations to facilitate the protection of genetic material. This is achieved by the sequestration of the telomeric sequence into a protective nucleoprotein cap that masks the ends from constitutive exposure to the DNA damage response machinery. When telomeres are unmasked, genome instability arises. Balancing capping requirements with telomere replication and the enzymatic processing steps that are obligatory for telomere function is a complex problem. Telomeric proteins and their interacting factors create an environment at chromosome ends that inhibits DNA repair; however, the repair machinery is essential for proper telomere function.
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Acknowledgements
R.O.S. is supported by the George E. Hewitt Foundation for Medical Research and J.K. acknowledges support by the National Institutes of Health (RO1 GM06525 and RO1 AG025837). We thank A. Cesare, D. Lackner, C. Naeger and L. Oganesian for images.
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DATABASES
OMIM
Autosomal dominant dyskeratosis congenita
X-linked recessive dyskeratosis congenita
FURTHER INFORMATION
Glossary
- G-quadruplex
-
A higher-order DNA structure consisting of G quartets in which guanosine residues are donors and acceptors in a G–G base pair. This structure is an obstacle to the moving replication fork.
- Fragile site
-
A site in a chromosome at which breaks frequently occur.
- Displacement loop
-
A single-stranded DNA loop, resulting from the invasion and pairing of a DNA end into homologous double-stranded sequences.
- Replicative senescence
-
A permanently differentiated state that cells enter when their telomeres become critically short or a threshold of DNA damage is exceeded.
- Homologous recombination
-
A repair pathway in which homologous sequences align and genetic information is copied from one DNA strand to the other.
- Werner syndrome
-
An inherited genetic disease that is characterized by premature-ageing symptoms and the early onset of cancer.
- Sister telomere loss
-
The loss of telomeric sequences from a single sister chromatid while the other telomere stays intact.
- Sister chromatid exchange
-
The HR-based exchange of DNA strands between sister chromatids.
- Nijmegen breakage syndrome
-
A rare syndrome characterized by chromosomal instability that is a result of mutations in the Nijmegen breakage syndrome 1 (NBS1; also known as NBN) gene.
- Ataxia telangiectasia
-
A rare, inherited disease, characterized by neurodegeneration, cancer susceptibility and radiation sensitivity, that is caused by mutations in the ATM gene.
- Non-reciprocal translocation
-
The transfer of genetic information from one non-homologous chromosome to another.
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O'Sullivan, R., Karlseder, J. Telomeres: protecting chromosomes against genome instability. Nat Rev Mol Cell Biol 11, 171–181 (2010). https://doi.org/10.1038/nrm2848
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DOI: https://doi.org/10.1038/nrm2848
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