Suppression of Nucleotide Metabolism Underlies the Establishment and Maintenance of Oncogene-Induced Senescence
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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2013-04-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124713001113 |
| _version_ | 1818808204907249664 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Katherine M. Aird |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-18T19:37:51Z |
| format | Article |
| id | doaj.art-c51fb2351544496e98a9bfbe85388849 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-18T19:37:51Z |
| publishDate | 2013-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-c51fb2351544496e98a9bfbe853888492022-12-21T20:55:33ZengElsevierCell Reports2211-12472013-04-01341252126510.1016/j.celrep.2013.03.004Suppression of Nucleotide Metabolism Underlies the Establishment and Maintenance of Oncogene-Induced SenescenceKatherine M. Aird0Gao Zhang1Hua Li2Zhigang Tu3Benjamin G. Bitler4Azat Garipov5Hong Wu6Zhi Wei7Stephan N. Wagner8Meenhard Herlyn9Rugang Zhang10Gene Expression and Regulation Program, The Wistar Institute Cancer Center, The Wistar Institute, Philadelphia, PA 19104, USATumor Microenvironment and Metastasis Program, The Wistar Institute Cancer Center, The Wistar Institute, Philadelphia, PA 19104, USAGene Expression and Regulation Program, The Wistar Institute Cancer Center, The Wistar Institute, Philadelphia, PA 19104, USAGene Expression and Regulation Program, The Wistar Institute Cancer Center, The Wistar Institute, Philadelphia, PA 19104, USAGene Expression and Regulation Program, The Wistar Institute Cancer Center, The Wistar Institute, Philadelphia, PA 19104, USAGene Expression and Regulation Program, The Wistar Institute Cancer Center, The Wistar Institute, Philadelphia, PA 19104, USADepartment of Pathology, Fox Chase Cancer Center, Philadelphia, PA 19111, USADepartment of Computer Science, New Jersey Institute of Technology, Newark, NJ 07102, USADivision of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, AustriaTumor Microenvironment and Metastasis Program, The Wistar Institute Cancer Center, The Wistar Institute, Philadelphia, PA 19104, USAGene Expression and Regulation Program, The Wistar Institute Cancer Center, The Wistar Institute, Philadelphia, PA 19104, USAOncogene-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.http://www.sciencedirect.com/science/article/pii/S2211124713001113 |
| spellingShingle | 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 Suppression of Nucleotide Metabolism Underlies the Establishment and Maintenance of Oncogene-Induced Senescence Cell Reports |
| title | Suppression of Nucleotide Metabolism Underlies the Establishment and Maintenance of Oncogene-Induced Senescence |
| title_full | Suppression of Nucleotide Metabolism Underlies the Establishment and Maintenance of Oncogene-Induced Senescence |
| title_fullStr | Suppression of Nucleotide Metabolism Underlies the Establishment and Maintenance of Oncogene-Induced Senescence |
| title_full_unstemmed | Suppression of Nucleotide Metabolism Underlies the Establishment and Maintenance of Oncogene-Induced Senescence |
| title_short | Suppression of Nucleotide Metabolism Underlies the Establishment and Maintenance of Oncogene-Induced Senescence |
| title_sort | suppression of nucleotide metabolism underlies the establishment and maintenance of oncogene induced senescence |
| url | http://www.sciencedirect.com/science/article/pii/S2211124713001113 |
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