ABSTRACT Approximately 20% of tumors contain activating mutations in the RAS family of oncogenes. As tumors progress to higher grades of malignancy, the expression of oncogenic RAS has been

reported to increase, leading to an oncogene-induced senescence (OIS) response. Evasion of this senescence barrier is a hallmark of advanced tumors indicating that OIS serves a critical

tumor-suppressive function. Induction of OIS has been attributed to either RAS-mediated production of reactive oxygen species (ROS) or to induction of a DNA damage response (DDR). However,

functional links between these two processes in triggering the senescent phenotype have not been explicitly described. Our previous work has shown that, in cultured untransformed cells,

affect the observed elevation in ROS levels produced by RAS oncoprotein expression. Conversely, we find that loss of MTH1 preferentially induces an _in vitro_ proliferation defect in

tumorigenic cells overexpressing oncogenic RAS. These results indicate that the guanine nucleotide pool is a critical target for intracellular ROS produced by oncogenic RAS and that

RAS-transformed cells require robust MTH1 expression to proliferate. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution

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about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS PPM1D ACTIVITY PROMOTES CELLULAR TRANSFORMATION BY PREVENTING SENESCENCE

AND CELL DEATH Article Open access 05 September 2024 ONCOGENIC RAS SENSITIZES CELLS TO DRUG-INDUCED REPLICATION STRESS VIA TRANSCRIPTIONAL SILENCING OF P53 Article Open access 07 April 2022

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8-oxoGTP by Ras, a small GTP-binding protein. _Biochem Biophys Res Commun_ 327: 342–348. Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS We are grateful to Anisleidys

Munoz for experimental assistance. We thank Dr Carlos Perez-Stable and Dr Ramiro Verdun for helpful comments on this manuscript. RAW is a Professor at American Cancer Society Research and at

Daniel K Ludwig Cancer Research. This work was supported by a Leukemia and Lymphoma Society Postdoctoral fellowship and a James and Esther King Florida Biomedical Research Program New

Investigator grant (to PR), a Howard Hughes Medical Institute summer undergraduate fellowship (to JJY) and grants from the Ellison Medical Foundation for Aging Research, The Ludwig Center

for Molecular Oncology and the Breast Cancer Research Fund (to RAW). AUTHOR INFORMATION Author notes * J J Young Present address: 5Current address: Department of Medicine, University of

California, San Francisco, CA, USA., * T T Onder Present address: 6Current address: Children's Hospital Boston, Harvard Medical School, Boston, MA, USA., AUTHORS AND AFFILIATIONS *

Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA P Rai, D G A Burton & M G Giribaldi * Whitehead

Institute for Biomedical Research, Cambridge, MA, USA J J Young, T T Onder & R A Weinberg * Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA J J Young, T

T Onder & R A Weinberg * Ludwig Center for Molecular Oncology, Cambridge, MA, USA R A Weinberg Authors * P Rai View author publications You can also search for this author inPubMed 

Google Scholar * J J Young View author publications You can also search for this author inPubMed Google Scholar * D G A Burton View author publications You can also search for this author

inPubMed Google Scholar * M G Giribaldi View author publications You can also search for this author inPubMed Google Scholar * T T Onder View author publications You can also search for this

author inPubMed Google Scholar * R A Weinberg View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to P Rai. ETHICS

DECLARATIONS COMPETING INTERESTS The authors declare no conflict of interest. ADDITIONAL INFORMATION Supplementary Information accompanies the paper on the Oncogene website SUPPLEMENTARY

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LEGENDS (DOC 93 KB) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Rai, P., Young, J., Burton, D. _et al._ Enhanced elimination of oxidized guanine

nucleotides inhibits oncogenic RAS-induced DNA damage and premature senescence. _Oncogene_ 30, 1489–1496 (2011). https://doi.org/10.1038/onc.2010.520 Download citation * Received: 21 March

2010 * Revised: 04 October 2010 * Accepted: 05 October 2010 * Published: 15 November 2010 * Issue Date: 24 March 2011 * DOI: https://doi.org/10.1038/onc.2010.520 SHARE THIS ARTICLE Anyone

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Springer Nature SharedIt content-sharing initiative KEYWORDS * cellular senescence * DNA damage * oxidative stress * 8-oxoguanine * MTH1 * RAS oncogene