Suppression of Nucleotide Metabolism Underlies the Establishment and Maintenance of Oncogene-Induced Senescence
Katherine M. Aird,
Gao Zhang,
Hua Li,
Zhigang Tu,
Benjamin G. Bitler,
Azat Garipov,
Hong Wu,
Zhi Wei,
Stephan N. Wagner,
Meenhard Herlyn,
Rugang Zhang
Affiliations
Katherine M. Aird
Gene Expression and Regulation Program, The Wistar Institute Cancer Center, The Wistar Institute, Philadelphia, PA 19104, USA
Gao Zhang
Tumor Microenvironment and Metastasis Program, The Wistar Institute Cancer Center, The Wistar Institute, Philadelphia, PA 19104, USA
Hua Li
Gene Expression and Regulation Program, The Wistar Institute Cancer Center, The Wistar Institute, Philadelphia, PA 19104, USA
Zhigang Tu
Gene Expression and Regulation Program, The Wistar Institute Cancer Center, The Wistar Institute, Philadelphia, PA 19104, USA
Benjamin G. Bitler
Gene Expression and Regulation Program, The Wistar Institute Cancer Center, The Wistar Institute, Philadelphia, PA 19104, USA
Azat Garipov
Gene Expression and Regulation Program, The Wistar Institute Cancer Center, The Wistar Institute, Philadelphia, PA 19104, USA
Hong Wu
Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
Zhi Wei
Department of Computer Science, New Jersey Institute of Technology, Newark, NJ 07102, USA
Stephan N. Wagner
Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
Meenhard Herlyn
Tumor Microenvironment and Metastasis Program, The Wistar Institute Cancer Center, The Wistar Institute, Philadelphia, PA 19104, USA
Rugang Zhang
Gene Expression and Regulation Program, The Wistar Institute Cancer Center, The Wistar Institute, Philadelphia, PA 19104, USA
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.
