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Telomere dysfunction and tumour suppression: the senescence connection

Nature Reviews Cancer volume 8, pages 450–458 (2008)Cite this article

Key Points

  • Telomeres are TTAGGG repetitive sequences that cap the ends of eukaryotic chromosomes.

  • A core of telomere binding proteins, termed the shelterin complex, serve to protect telomeric ends.

  • Critical telomere shortening or uncapping of telomere binding proteins results in telomere dysfunction.

  • Dysfunctional telomeres activate a DNA damage response. In the setting of a competent p53 pathway, this initiates senescence and apoptotic programmes to inhibit tumorigenesis.

  • In cells with mutant p53, dysfunctional telomeres promote genome instability and progression to cancer.

  • Cellular senescence is as potent as apoptosis in suppressing spontaneous tumorigenesis in mouse models of telomere dysfunction.

Abstract

Long-lived organisms such as humans have evolved several intrinsic tumour suppressor mechanisms to combat the slew of oncogenic somatic mutations that constantly arise in proliferating stem-cell compartments. One of these anticancer barriers is the telomere, a specialized nucleoprotein complex that caps the ends of eukaryotic chromosome. Impaired telomere function activates the canonical DNA damage response pathway that engages p53 to initiate apoptosis or replicative senescence. Here, we discuss how p53-dependent senescence induced by dysfunctional telomeres may be as potent as apoptosis in suppressing tumorigenesis in vivo.

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Figure 1: Telomere structure.
Figure 2: Telomere dysfunction activates the p53 and RB pathways.
Figure 3: Activation of cellular senescence suppresses tumorigenesis in vivo.

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Acknowledgements

S.C acknowledges generous financial support from the NIA (RO1 AG028888), the NCI (RO1 CA129037), the Welch Foundation, the Elsa U. Pardee Foundation, the Sydney Kimmel Foundation for Cancer Research, the Abraham and Phyllis Katz Foundation, and the Michael Kadoorie Cancer Genetic Research Program. Y.D. is supported by a NCI Howard Temin Award (1K01CA124461) and S.S.C is supported by a NIH Predoctoral Training Grant.

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Authors and Affiliations

  1. Department of Cancer Genetics, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, 77030, Texas, USA

    Yibin Deng, Suzanne S. Chan & Sandy Chang

  2. Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, 77030, Texas, USA

    Sandy Chang

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  1. Yibin Deng
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DATABASES

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breast carcinoma

HCC

skin carcinoma

SCC

National Cancer Institute Drug Dictionary

GRN163L

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Glossary

Breakage–fusion–bridge cycle

Chromosomal ends with critically shortened telomeres are highly recombinogenic, and undergo repeated cycles of end-to-end fusions, followed by random breakage, and then subsequent fusions to generate loss of heterozygosity or amplification of certain chromosomal loci.

Dicentric chromosome

A chromosome that has two centromeres, formed by breakage and reunion of two chromosomes.

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Deng, Y., Chan, S. & Chang, S. Telomere dysfunction and tumour suppression: the senescence connection. Nat Rev Cancer 8, 450–458 (2008). https://doi.org/10.1038/nrc2393

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