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Replicative Senescence as an Intrinsic Tumor-Suppressor Mechanism

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Cellular Senescence and Tumor Suppression

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Abstract

One feature of human carcinomas is their strikingly complex cytogenetic profiles. An important mechanism that can give rise to this level of genomic instability is the functional status of telomeres, the protein-DNA complexes that cap the ends of chromosomes. Telomeres serve to protect eukaryotic chromosomal ends from being recognized as damaged DNA, and growing evidence suggests that critically shortened (dysfunctional) telomeres may help initiate the onset of cancer. Dysfunctional telomeres potently engage the DNA damage response pathway, leading to the onset of cellular senescence when p53 is functional. However, in the absence of p53, dysfunctional telomeres can initiate cancer by promoting genomic instability. In this chapter, I will use mouse models to illustrate the interplay between telomere dysfunction and the development of carcinomas in the setting of an intact or mutated p53-dependent DDR pathway. Dysfunctional telomeres trigger senescence when p53 is functional, thereby protecting epithelial tissues from cancer progression. These results suggest that p53-dependent senescence, induced by dysfunctional telomeres, may be as potent as apoptosis in suppressing tumorigenesis in vivo.

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Abbreviations

ALT:

Alternative lengthening of telomeres

ATM:

Ataxia-telangiectasia mutated

ATR:

Ataxia-telangiectasia and Rad3 related

BFB:

Breakage-fusion-bridge

DDR:

DNA damage response

DSBs:

DNA double stranded breaks

HDFs:

Human diploid fibroblasts

HR:

Homologous recombination

LOH:

Loss of heterozygosity

MDM2:

Murine double minute 2

NHEJ:

Nonhomologous end joining

NRTs:

Nonreciprocal translocations

OB:

Fold-oligosaccharide/oligonucleotide-binding fold

POT1:

Protection of telomeres 1

SA-β-gal:

Senescence-associated β-galactosidase

Terc:

Telomerase RNA template

Tert:

Telomerase reverse transcriptase

TIN2:

TRF1 interacting protein 2

TRF1:

Telomeric-repeat binding factor 1

TRF2:

Telomeric-repeat binding factor 2

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Authors and Affiliations

  1. Department of Genetics, Unit 1006, U.T.M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA

    Sandy Chang

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  1. Sandy Chang
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Correspondence to Sandy Chang .

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Editors and Affiliations

  1. Cancer Research UK, University of Glasgow, Switchback Road, Glasgow, G61 1BD, United Kingdom

    Peter D. Adams

  2. Dept. Molecular & Cell Biology &, Brown University, Ship Street 70, Providence, 02912, U.S.A.

    John M. Sedivy

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Chang, S. (2010). Replicative Senescence as an Intrinsic Tumor-Suppressor Mechanism. In: Adams, P., Sedivy, J. (eds) Cellular Senescence and Tumor Suppression. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-1075-2_8

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