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Role of MUTYH and MSH2 in the Control of Oxidative DNA Damage, Genetic Instability, and Tumorigenesis

¹ Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Rome, Italy; ² Department of Translational Oncology, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy; ³ Department of Genetics and Microbiology, University of Pavia, Pavia, Italy; and ⁴ Centro Studi per l'Invecchiamento, Università degli Studi "G. d'Annunzio," Chieti-Pescara, Italy

Requests for reprints: Margherita Bignami, Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Roma, Italy. Phone: 39-6-49902355; Fax: 39-6-49903650; E-mail: bignami{at}iss.it.

Key Words: Mutyh • Msh2 • mismatch repair • mutation rates • 8-oxoguanine

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 Msh2 mismatch repair gene is associated with a mutator phenotype and increased cancer susceptibility. The base excision repair gene Mutyh 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 in vitro and in vivo. Msh2^–/– mouse embryo fibroblasts (MEF) showed a strong mutator phenotype at the hprt gene, whereas Mutyh inactivation was associated with a milder phenotype (2.9 x 10^–6 and 3.3 x 10^–7 mutation/cell/generation, respectively). The value of 2.7 x 10^–6 mutation/cell/generation in Msh2^–/–Mutyh^–/– MEFs did not differ significantly from Msh2^–/– 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 Msh2^–/–Mutyh^–/– animals, suggesting that in vivo 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 Msh2^–/–Mutyh^–/– when compared with Msh2^–/– 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 Msh2^–/– mice depends on Mutyh activity. [Cancer Res 2009;69(10):4372–9]