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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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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