Journal
CELL REPORTS
Volume 3, Issue 4, Pages 1252-1265Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2013.03.004
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Funding
- NIH/NCI [R01CA160331, T32CA9171-35]
- DoD Ovarian Cancer Academy Award [OC093420]
- FWF-Austrian Science Fund [L590-B12]
- Cancer Center Support Grant [CA010815]
- Austrian Science Fund (FWF) [L 590] Funding Source: researchfish
- Austrian Science Fund (FWF) [L590] Funding Source: Austrian Science Fund (FWF)
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Oncogene-induced senescence is characterized by a stable cell growth arrest, thus providing a tumor suppression mechanism. However, the underlying mechanisms for this phenomenon remain unknown. Here, we show that a decrease in growth arrest. The decrease in dNTP levels is caused by oncogene-induced repression of ribonucleotide reductase subunit M2 (RRM2), a rate-limiting protein in dNTP synthesis. This precedes the senescence-associated cell-cycle exit and coincides with the DNA damage response. Consistently, RRM2 down-regulation is both necessary and sufficient for senescence. Strikingly, suppression of nucleotide metabolism by RRM2 repression is also necessary for maintenance of the stable senescence-associated cell growth arrest. Furthermore, RRM2 repression correlates with senescence status in benign nevi and melanoma, and its knockdown drives senescence of melanoma cells. These data reveal the molecular basis whereby the stable growth arrest of oncogene-induced senescence is established and maintained through suppression of nucleotide metabolism.
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