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

研究成果: ジャーナルへの寄稿記事

104 引用 (Scopus)

抄録

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.

元の言語英語
ページ(範囲)465-474
ページ数10
ジャーナルMolecular and cellular biology
24
発行部数1
DOI
出版物ステータス出版済み - 1 1 2004

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DNA Mismatch Repair
Mutation Rate
Purines
Microsatellite Instability
Phenotype
Incidence
DNA Damage
Colorectal Neoplasms
Prostatic Neoplasms
Fibroblasts
Cell Line
Mutation
DNA
triphosphoric acid
Neoplasms
Proteins

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

これを引用

The Oxidized Deoxynucleoside Triphosphate Pool Is a Significant Contributor to Genetic Instability in Mismatch Repair-Deficient Cells. / Russo, Maria Teresa; Blasi, Monica Francesca; Chiera, Federica; Fortini, Paola; Degan, Paolo; Macpherson, Peter; Furuichi, Masato; Nakabeppu, Yusaku; Karran, Peter; Aquilina, Gabriele; Bignami, Margherita.

:: Molecular and cellular biology, 巻 24, 番号 1, 01.01.2004, p. 465-474.

研究成果: ジャーナルへの寄稿記事

Russo, Maria Teresa ; Blasi, Monica Francesca ; Chiera, Federica ; Fortini, Paola ; Degan, Paolo ; Macpherson, Peter ; Furuichi, Masato ; Nakabeppu, Yusaku ; Karran, Peter ; Aquilina, Gabriele ; Bignami, Margherita. / The Oxidized Deoxynucleoside Triphosphate Pool Is a Significant Contributor to Genetic Instability in Mismatch Repair-Deficient Cells. :: Molecular and cellular biology. 2004 ; 巻 24, 番号 1. pp. 465-474.
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