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Molecular and Cellular Biology, January 2004, p. 465-474, Vol. 24, No. 1
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.1.465-474.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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

Maria Teresa Russo,1,{dagger} Monica Francesca Blasi,1,{dagger} Federica Chiera,1 Paola Fortini,1 Paolo Degan,2 Peter Macpherson,3 Masato Furuichi,4 Yusaku Nakabeppu,4 Peter Karran,3 Gabriele Aquilina,1 and Margherita Bignami1*

Chemical Carcinogenesis Unit, Istituto Superiore di Sanità, Rome,1 Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy,2 Clare Hall Laboratories, Cancer Research UK London Research Institute, South Mimms, United Kingdom,3 Department of Biochemistry, Kyushu University, Fukuoka, Japan4

Received 6 August 2003/ Returned for modification 10 September 2003/ Accepted 18 September 2003

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.

* Corresponding author. Mailing address: Chemical Carcinogenesis Unit, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. Phone: 0039-06-49902355. Fax: 0039-06-49902580. E-mail: bignami{at}iss.it.

{dagger} M.T.R. and M.F.B. contributed equally to this work.

Molecular and Cellular Biology, January 2004, p. 465-474, Vol. 24, No. 1
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.1.465-474.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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