Telomeres are essential nucleoprotein structures that protect chromosome ends. In mammals, telomeres are composed of TTAGGG repeats, which are bound by a protein complex termed shelterin.
Cell divisions lead to the progressive erosion of telomeric repeats. When telomeres become too short to recruit the shelterin complex, they become dysfunctional, leading to telomere deprotection.
Chromosome ends with dysfunctional telomeres are detected as sites of DNA damage, leading to the activation of the DNA damage response (DDR). In humans, telomere dysfunction features in inherited diseases such as dyskeratosis congenita, which are characterized by defects in the regulation of telomere length.
Several DDR pathways are engaged in the processing of deprotected telomeres, including the classical and alternative non-homologous end joining (NHEJ) pathways and the homologous recombination pathway. Studies aimed at defining how functional telomeres suppress these pathways have been instrumental in shedding light on the regulation of these crucial cellular processes.
Telomere deprotection and activation of telomere elongation pathways have a crucial role in the development of human cancers. Telomere erosion in proliferating pre-neoplastic cells functions as a tumour suppressor mechanism that cancer cells can bypass by engaging telomere elongation pathways.
The recent identification of mutations affecting telomere-associated proteins in cancer samples suggests that telomere deprotection has a crucial role in tumour progression. In agreement with this, mounting evidence suggests that in human cancers, aberrant DNA damage repair triggered at deprotected telomeres promotes genomic instability.
Mammalian cells have evolved specialized mechanisms to sense and repair double-strand breaks (DSBs) to maintain genomic stability. However, in certain cases, the activity of these pathways can lead to aberrant DNA repair, genomic instability and tumorigenesis. One such case is DNA repair at the natural ends of linear chromosomes, known as telomeres, which can lead to chromosome-end fusions. Here, we review data obtained over the past decade and discuss the mechanisms that protect mammalian chromosome ends from the DNA damage response. We also discuss how telomere research has helped to uncover key steps in DSB repair. Last, we summarize how dysfunctional telomeres and the ensuing genomic instability drive the progression of cancer.
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The authors apologize to the colleagues whose work they could not cite owing to space constraints. They thank A. Penev, S. K. Deng, Lynda Groocock, F. Lottersberger and D. Conomos for comments on the manuscript. Research in the authors' laboratories is supported by grants from the US National Institutes of Health (DP2CA195767 and DK102562 to A.S., and AG038677 to E.L.D.) and the American Cancer Society (RSG-14-186) to E.L.D. A.S. is a Pew-Stewart Scholar, a Damon Runyon-Rachleff grant recipient and a fellow of the David and Lucille Packard foundation.
The authors declare no competing financial interests.
- DNA damage response
(DDR). A collection of pathways that sense, signal and repair DNA lesions.
- Dicentric chromosomes
Aberrant chromosomes with two centromeres, resulting from the fusion of two chromosomes.
A mechanism producing chromosomal instability, triggered by the fusion of deprotected telomeres, which leads to repeating cycles of chromosome breakage and fusion.
- Fragile telomeres
Breaks or gaps at telomeres of metaphase chromosomes, caused by replication stress.
- Fragile sites
Genomic regions that appear as gaps or breaks on metaphase chromosomes when DNA replication is partially inhibited.
- ALT-associated PML bodies
(APBs). Promyelocytic leukaemia (PML) bodies are dynamic protein aggregates within the nuclei of some cells that contain the PML protein. Alternative lengthening of telomeres (ALT)-associated PML bodies are found exclusively in cancer cells, which rely on the ALT pathway to maintain telomeres.
- Quantitative telomeric chromatin isolation protocol
(QTIP). A telomere-protein purification method used to quantify changes in the content of telomeric chromatin.
- Proteomics of isolated chromatin segments
(PICh). A method to identify proteins associated with specific genomic loci that are rich in repetitive DNA.
- Telomere biology disorder
(TBD). One of a set of pathologies that are defined by the presence of short telomeres.
A mutational phenomenon that involves catastrophic shattering and rebuilding of chromosomes, leading to multiple clustered chromosomal rearrangements.
Clustered point mutations that localize to particular regions of certain cancer genomes.
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Lazzerini-Denchi, E., Sfeir, A. Stop pulling my strings — what telomeres taught us about the DNA damage response. Nat Rev Mol Cell Biol 17, 364–378 (2016). https://doi.org/10.1038/nrm.2016.43
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