The Oxidized Deoxynucleoside Triphosphate Pool Is a Significant Contributor to Genetic Instability in Mismatch Repair-Deficient Cells

Maria Teresa Russo, Monica Francesca Blasi, Federica Chiera, Paola Fortini, Paolo Degan, Peter Macpherson, Masato Furuichi, Yusaku Nakabeppu, Peter Karran, Gabriele Aquilina, Margherita Bignami

Research output: Contribution to journalArticle

105 Citations (Scopus)

Abstract

Oxidation is a common form of DNA damage to which purines are particularly susceptible. We previously reported that oxidized dGTP is potentially an important source of DNA 8-oxodGMP in mammalian cells and that the incorporated lesions are removed by DNA mismatch repair (MMR). MMR deficiency is associated with a mutator phenotype and widespread microsatellite instability (MSI). Here, we identify oxidized deoxynucleoside triphosphates (dNTPs) as an important cofactor in this genetic instability. The high spontaneous hprt mutation rate of MMR-defective msh2-/- mouse embryonic fibroblasts was attenuated by expression of the hMTH1 protein, which degrades oxidized purine dNTPs. A high level of hMTH1 abolished their mutator phenotype and restored the hprt mutation rate to normal. Molecular analysis of hprt mutants showed that the presence of hMTH1 reduced the incidence of mutations in all classes, including frameshifts, and also implicated incorporated 2-oxodAMP in the mutator phenotype. In hMSH6-deficient DLD-1 human colorectal carcinoma cells, overexpression of hMTH1 markedly attenuated the spontaneous mutation rate and reduced MSI. It also reduced the incidence of -G and -A frameshifts in the hMLH1-defective DU145 human prostatic cancer cell line. Our findings indicate that incorporation of oxidized purines from the dNTP pool may contribute significantly to the extreme genetic instability of MMR-defective human tumors.

Original languageEnglish
Pages (from-to)465-474
Number of pages10
JournalMolecular and cellular biology
Volume24
Issue number1
DOIs
Publication statusPublished - Jan 2004

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'The Oxidized Deoxynucleoside Triphosphate Pool Is a Significant Contributor to Genetic Instability in Mismatch Repair-Deficient Cells'. Together they form a unique fingerprint.

  • Cite this