Abstract
<div>Abstract<p>Mismatch repair is the major pathway controlling genetic stability by removing mispairs caused by faulty replication and/or mismatches containing oxidized bases. Thus, inactivation of the <i>Msh2</i> mismatch repair gene is associated with a mutator phenotype and increased cancer susceptibility. The base excision repair gene <i>Mutyh</i> is also involved in the maintenance of genomic integrity by repairing premutagenic lesions induced by oxidative DNA damage. Because evidence in bacteria suggested that Msh2 and Mutyh repair factors might have some overlapping functions, we investigated the biological consequences of their single and double inactivation <i>in vitro</i> and <i>in vivo. Msh2<sup>−/−</sup></i> mouse embryo fibroblasts (MEF) showed a strong mutator phenotype at the <i>hprt</i> gene, whereas <i>Mutyh</i> inactivation was associated with a milder phenotype (2.9 × 10<sup>−6</sup> and 3.3 × 10<sup>−7</sup> mutation/cell/generation, respectively). The value of 2.7 × 10<sup>−6</sup> mutation/cell/generation in <i>Msh2<sup>−/−</sup>Mutyh<sup>−/−</sup></i> MEFs did not differ significantly from <i>Msh2<sup>−/−</sup></i> cells. When steady-state levels of DNA 8-oxo-7,8-dihydroguanine (8-oxoG) were measured in MEFs of different genotypes, single gene inactivation resulted in increases similar to those observed in doubly defective cells. In contrast, a synergistic accumulation of 8-oxoG was observed in several organs of <i>Msh2<sup>−/−</sup>Mutyh<sup>−/−</sup></i> animals, suggesting that <i>in vivo</i> Msh2 and Mutyh provide separate repair functions and contribute independently to the control of oxidative DNA damage. Finally, a strong delay in lymphomagenesis was observed in <i>Msh2<sup>−/−</sup>Mutyh<sup>−/−</sup></i> when compared with <i>Msh2<sup>−/−</sup></i> animals. The immunophenotype of these tumors indicate that both genotypes develop B-cell lymphoblastic lymphomas displaying microsatellite instability. This suggests that a large fraction of the cancer-prone phenotype of <i>Msh2<sup>−/−</sup></i> mice depends on Mutyh activity. [Cancer Res 2009;69(10):4372–9]</p></div>
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