Suppression of nucleotide metabolism underlies the establishment and maintenance of oncogene-induced senescence

Cell Rep. 2013 Apr 25;3(4):1252-65. doi: 10.1016/j.celrep.2013.03.004. Epub 2013 Apr 4.


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 deoxyribonucleotide triphosphate (dNTP) levels underlies oncogene-induced stable senescence-associated cell 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 downregulation 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Cycle Checkpoints / drug effects
  • Cell Line
  • Cellular Senescence*
  • DNA Repair / drug effects
  • Down-Regulation
  • E2F7 Transcription Factor / genetics
  • E2F7 Transcription Factor / metabolism
  • Humans
  • Nucleosides / pharmacology
  • Oncogenes / genetics*
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins B-raf / metabolism
  • Purine Nucleotides / metabolism*
  • Pyrimidine Nucleotides / metabolism*
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Ribonucleoside Diphosphate Reductase / antagonists & inhibitors
  • Ribonucleoside Diphosphate Reductase / genetics
  • Ribonucleoside Diphosphate Reductase / metabolism
  • ras Proteins / genetics
  • ras Proteins / metabolism


  • E2F7 Transcription Factor
  • Nucleosides
  • Purine Nucleotides
  • Pyrimidine Nucleotides
  • RNA, Small Interfering
  • ribonucleotide reductase M2
  • Ribonucleoside Diphosphate Reductase
  • Proto-Oncogene Proteins B-raf
  • ras Proteins