title: Suppression of nucleotide metabolism underlies the establishment and maintenance of oncogene-induced senescence.
abstract: 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.
authors.affiliation: Gene Expression and Regulation Program, The Wistar Institute Cancer Center, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Aird
authors.forename: Gao
authors.initials: G
authors.lastname: Zhang
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Tu
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Bitler
authors.forename: Azat
authors.initials: A
authors.lastname: Garipov
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.forename: Zhi
authors.initials: Z
authors.lastname: Wei
authors.forename: Stephan N
authors.initials: SN
authors.lastname: Wagner
authors.forename: Meenhard
authors.initials: M
authors.lastname: Herlyn
authors.forename: Rugang
authors.initials: R
authors.lastname: Zhang
mesh_terms: D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002460:Cell Line; D016922:Cellular Senescence; D004260:DNA Repair / Q000187:drug effects; D015536:Down-Regulation; D050702:E2F7 Transcription Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009705:Nucleosides / Q000494:pharmacology; D009857:Oncogenes / Q000235:genetics*; D011401:Promoter Regions, Genetic; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D011685:Purine Nucleotides / Q000378:metabolism*; D011742:Pyrimidine Nucleotides / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012262:Ribonucleoside Diphosphate Reductase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D050702:E2F7 Transcription Factor; D009705:Nucleosides; D011685:Purine Nucleotides; D011742:Pyrimidine Nucleotides; D034741:RNA, Small Interfering; C093713:ribonucleotide reductase M2; D012262:Ribonucleoside Diphosphate Reductase; D048493:Proto-Oncogene Proteins B-raf; D018631:ras Proteins
references.citation: Annu Rev Biochem. 1988;57:349-74
references.pmid: 3052277
references.citation: Nat Protoc. 2009;4(12):1798-806
references.pmid: 20010931
references.citation: Nature. 2006 Nov 30;444(7119):638-42
references.pmid: 17136094
references.citation: Nucleic Acids Res. 2011 Sep 1;39(17):e112
references.pmid: 21576234
references.citation: Nature. 2005 Aug 4;436(7051):720-4
references.pmid: 16079850
references.citation: Genes Dev. 2012 Jul 15;26(14):1546-57
references.pmid: 22802529
references.citation: J Biol Chem. 2004 May 7;279(19):20067-75
references.pmid: 14982920
references.citation: Cell. 2005 Feb 25;120(4):513-22
references.pmid: 15734683
references.citation: N Engl J Med. 2006 Sep 7;355(10):1037-46
references.pmid: 16957149
references.citation: Int J Cancer. 1993 Jun 19;54(4):693-9
references.pmid: 8514460
references.citation: Genes Dev. 2007 Feb 15;21(4):379-84
references.pmid: 17299132
references.citation: Cancer Cell. 2009 Apr 7;15(4):294-303
references.pmid: 19345328
references.citation: Cell. 2011 Apr 29;145(3):435-46
references.pmid: 21529715
references.citation: Proc Natl Acad Sci U S A. 1995 Sep 26;92(20):9363-7
references.pmid: 7568133
references.citation: Nat Cell Biol. 2009 Aug;11(8):973-9
references.pmid: 19597488
references.citation: Nature. 2006 Nov 30;444(7119):633-7
references.pmid: 17136093
references.citation: Cell. 1997 Mar 7;88(5):593-602
references.pmid: 9054499
references.citation: Cancer Res. 1994 Oct 15;54(20):5269-72
references.pmid: 7923152
references.citation: Mol Cell Biol. 2007 Mar;27(6):2343-58
references.pmid: 17242207
references.citation: Mol Cancer Res. 2010 Dec;8(12):1610-8
references.pmid: 21115743
references.citation: Nat Rev Mol Cell Biol. 2007 Sep;8(9):729-40
references.pmid: 17667954
references.citation: Dev Cell. 2005 Jan;8(1):19-30
references.pmid: 15621527
references.citation: Cold Spring Harb Symp Quant Biol. 2011;76:369-74
references.pmid: 21960526
references.citation: J Biol Chem. 2006 Mar 24;281(12):7834-41
references.pmid: 16436374
references.citation: Mol Cell Biol. 2007 Feb;27(3):949-62
references.pmid: 17101789
references.citation: Nat Rev Cancer. 2009 Nov;9(11):785-97
references.pmid: 19851314
references.citation: Cancer Res. 2008 Apr 15;68(8):2652-60
references.pmid: 18413732
references.citation: Annu Rev Biochem. 2006;75:681-706
references.pmid: 16756507
references.citation: Mol Cell Biol. 1999 Jan;19(1):1-11
references.pmid: 9858526
references.citation: Oncogene. 2008 May 1;27(20):2801-9
references.pmid: 18193093
references.citation: Cell. 2007 Jan 26;128(2):233-4
references.pmid: 17254959
references.citation: Cell. 2003 Jun 13;113(6):703-16
references.pmid: 12809602
references.citation: Genes Dev. 2010 Nov 15;24(22):2463-79
references.pmid: 21078816
references.citation: PLoS One. 2008 Jul 16;3(7):e2722
references.pmid: 18628958
references.citation: Cell. 2012 May 25;149(5):1023-34
references.pmid: 22632967
references.citation: J Biol Chem. 1985 Aug 5;260(16):9114-6
references.pmid: 3894352
references.citation: Mol Cell. 2007 Jul 20;27(2):183-96
references.pmid: 17643369
references.citation: Dev Cell. 2011 Dec 13;21(6):1077-91
references.pmid: 22137763
references.citation: Mol Cancer Ther. 2006 Nov;5(11):2606-12
references.pmid: 17088437