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Genetic instability as a consequence of inappropriate entry into and Progression through S-phase

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Summary

The stability of the mammalian genome depends on the proper function of G1 and G2 cell cycle control mechanisms. Two tumor suppressors, p53 and retinoblastoma (Rb), play key roles in progression from G1 into S-phase. We address the mechanisms by which these proteins mediate a G1 arrest in response to DNA damage and limiting metabolic conditions. Gamma-irradiation induced a prolonged, p53-dependent G1 arrest associated with a long-term increase in the levels of the cdk-inhibitor p21WAF1/Cip1 (p21). Microinjection of linear plasmid DNA also caused a G1 arrest. The p53-dependent arrest induced by inhibitors of UMP biosynthesis was reversible and occurred in the absence of detectable DNA damage. Both arrest mechanisms contribute to limiting the formation and propagation of damaged genomes. Cells containing mutant p53 but wild-type Rb do not generate methotrexate (Mtx) resistant variants. However, pre-treatment with DNA damaging agents prior to drug selection resulted in resistant clones containing amplified dihydrofolate reductase (DHFR) genes, suggesting that DNA breakage is a rate limiting step for gene amplification. The Mtx-induced arrest did not occur in cells with non-functional Rb. Rb acts as a negative regulator of the E2F transcription factors, and Rb-deficient primary mouse embryo fibroblasts (MEFs) produced elevated levels of mRNA and protein for key E2F target genes. Failure to prevent entry into S-phase in Rb−/- MEFs exposed to DNA-damaging or nutrient limiting conditions caused apoptosis and correlated with p53 induction. Taken together, these findings indicate a link between p53 and Rb function and suggest that their coordination insures correct entry into S-phase, minimizing the emergence of genetic variants.

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  1. Alex Almasan

    Present address: Departments of Radiation Oncology and Cancer Biology, Cleveland Clinic Foundation, Cleveland, Ohio, USA

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  1. Gene Expression Laboratory, The Salk Institute, 10010 N. Torrey Pines Rd., 92037, La Jolla, CA, USA

    Alex Almasan, Steven P. Linke, Thomas G. Paulson, Li-chun Huang & Geoffrey M. Wahl

  2. Department of Biology, University of California, San Diego, La Jolla, Califonia, USA

    Steven P. Linke & Thomas G. Paulson

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Almasan, A., Linke, S.P., Paulson, T.G. et al. Genetic instability as a consequence of inappropriate entry into and Progression through S-phase. Cancer Metast Rev 14, 59–73 (1995). https://doi.org/10.1007/BF00690212

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