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Telomeres in cancer: tumour suppression and genome instability

An Author Correction to this article was published on 28 February 2019

Key Points

  • Telomeres sustain the proliferative capacity of cells and maintain genome integrity by ensuring that chromosome ends are not mistaken for sites of DNA damage. Chromosome end protection is achieved by the telomeric shelterin complex, which suppresses DNA damage signalling and repair pathways.

  • In telomerase-negative cells, telomeres shorten during cell proliferation owing to incomplete DNA replication and exonucleolytic processing. This attrition compromises telomere function leading to signalling by the kinases ATM and ATR, cell cycle arrest and senescence or apoptosis.

  • Telomere attrition represents a major barrier to tumorigenesis, operating as a tumour suppressor pathway.

  • Loss of the RB and p53 pathways disables the ability of cells to arrest following ATR and ATM signalling at telomeres that were compromised by attrition.

  • RB-deficient and p53-deficient cells continue to experience telomere shortening, which leads to telomere crisis.

  • Telomere crisis can cause a wide array of genomic aberrations, including chromosome deletions and amplifications, translocations, chromothripsis, kataegis and tetraploidization.

  • Telomere crisis has been documented in many cancers, including chronic lymphocytic leukaemia, breast cancer and colorectal adenomas.

  • Activation of telomerase provides an escape from crisis and allows outgrowth of cells with a rearranged genome.

Abstract

The shortening of human telomeres has two opposing effects during cancer development. On the one hand, telomere shortening can exert a tumour-suppressive effect through the proliferation arrest induced by activating the kinases ATM and ATR at unprotected chromosome ends. On the other hand, loss of telomere protection can lead to telomere crisis, which is a state of extensive genome instability that can promote cancer progression. Recent data, reviewed here, provide new evidence for the telomere tumour suppressor pathway and has revealed that telomere crisis can induce numerous cancer-relevant changes, including chromothripsis, kataegis and tetraploidization.

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Figure 1: Composition and structure of the human telomere system.
Figure 2: Telomere shortening as a barrier to tumorigenesis.
Figure 3: Telomere crisis.
Figure 4: BFB cycles and chromosomal rearrangements during telomere crisis.
Figure 5: Chromothripsis and kataegis in telomere crisis.
Figure 6: Tetraploidization during telomere crisis.

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Acknowledgements

The authors thank S. Yu and the de Lange laboratory for discussions and help with this manuscript. The authors' work is supported by grants from the US National Institutes of Health (CA181090, AG016642 and K99CA212290), the STARR Cancer Consortium and the Breast Cancer Research Foundation.

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PowerPoint slides

Glossary

ATM

A PI3K-related protein kinase that initiates the response to double-strand breaks, with crucial roles in cell cycle regulation and DNA repair.

ATR

A PI3K-related protein kinase that responds to the formation of single-stranded DNA, with a crucial role in the response to replication stress and double-strand breaks.

Non-homologous end joining

A major double-strand break repair pathway that does not rely on sequence homology and can result in small insertions and deletions at the site of repair.

Hayflick limit

The finite proliferation potential of primary human cells.

Dicentric chromosomes

Abnormal chromosomes with two centromeres that can result from telomere–telomere fusion.

Break-induced replication

An origin of replication-independent replication restart that is initiated by the invasion of resected DNA into homologous sequences.

Micronuclei

Abnormal, small nuclei containing one or more chromosome (fragments); often formed as a result of mitotic chromosome segregation defects.

Lamin

An intermediate filament protein that imparts structural rigidity to the nucleus by assembling into a meshwork at the inner nuclear membrane.

Hyper-triploid karyotype

A genome that contains more than three (3N) but less than four (4N) sets of chromosomes.

Anaphase bridges

DNA bridges that connect chromatin masses undergoing separation during anaphase and can be observed with conventional DNA staining techniques.

Usual ductal hyperplasia

A benign overgrowth of cells that line the ducts or milk glands and is associated with an elevated risk of breast cancer.

Ductal carcinoma in situ

A noninvasive, early form of breast cancer characterized by proliferative, malignant cells that are confined to the milk duct.

Alternative lengthening of telomeres

A telomere lengthening mechanism that relies on homologous recombination-mediated DNA copying to counteract telomere shortening.

Chromoplexy

A class of complex DNA rearrangements frequently observed in prostate cancer, which is characterized by multiple chromatin rearrangements that arise in a highly interdependent manner.

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Maciejowski, J., de Lange, T. Telomeres in cancer: tumour suppression and genome instability. Nat Rev Mol Cell Biol 18, 175–186 (2017). https://doi.org/10.1038/nrm.2016.171

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