Enhanced elimination of oxidized guanine nucleotides inhibits oncogenic RAS-induced DNA damage and premature senescence

Priyamvada Rai, J. J. Young, D. G A Burton, M. G. Giribaldi, T. T. Onder, R. A. Weinberg

Research output: Contribution to journalArticle

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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, preventing elimination of oxidized guanine deoxyribonucleotides, which was achieved by suppressing expression of the cellular 8-oxo-dGTPase, human MutT homolog 1 (MTH1), sufficed to induce a DDR as well as premature senescence. Here, we demonstrate that overexpression of MTH1 can prevent the oncogenic H-RAS-induced DDR and attendant premature senescence, although it does not 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.

Original languageEnglish
Pages (from-to)1489-1496
Number of pages8
JournalOncogene
Volume30
Issue number12
DOIs
StatePublished - Mar 24 2011

Fingerprint

Guanine Nucleotides
DNA Damage
Oncogenes
Reactive Oxygen Species
Neoplasms
Deoxyribonucleotides
Oncogene Proteins
Guanine
Cultured Cells
Phenotype
Mutation

Keywords

  • 8-oxoguanine
  • cellular senescence
  • DNA damage
  • MTH1
  • oxidative stress
  • RAS oncogene

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Rai, P., Young, J. J., Burton, D. G. A., Giribaldi, M. G., Onder, T. T., & Weinberg, R. A. (2011). Enhanced elimination of oxidized guanine nucleotides inhibits oncogenic RAS-induced DNA damage and premature senescence. Oncogene, 30(12), 1489-1496. https://doi.org/10.1038/onc.2010.520

Enhanced elimination of oxidized guanine nucleotides inhibits oncogenic RAS-induced DNA damage and premature senescence. / Rai, Priyamvada; Young, J. J.; Burton, D. G A; Giribaldi, M. G.; Onder, T. T.; Weinberg, R. A.

In: Oncogene, Vol. 30, No. 12, 24.03.2011, p. 1489-1496.

Research output: Contribution to journalArticle

Rai, Priyamvada ; Young, J. J. ; Burton, D. G A ; Giribaldi, M. G. ; Onder, T. T. ; Weinberg, R. A. / Enhanced elimination of oxidized guanine nucleotides inhibits oncogenic RAS-induced DNA damage and premature senescence. In: Oncogene. 2011 ; Vol. 30, No. 12. pp. 1489-1496.
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