RESUMEN
Cancer predisposition in hereditary non-polyposis colon cancer (HNPCC) is caused by defects in DNA mismatch repair (MMR). Mismatch recognition is attributed to two heterodimeric protein complexes: MutSalpha (refs 2, 3, 4, 5), a dimer of MutS homologues MSH2 and MSH6; and MutSbeta (refs 2,7), a dimer of MSH2 and MSH3. These complexes have specific and redundant mismatch recognition capacity. Whereas MSH2 deficiency ablates the activity of both dimers, causing strong cancer predisposition in mice and men, loss of MSH3 or MSH6 (also known as GTBP) function causes a partial MMR defect. This may explain the rarity of MSH6 and absence of MSH3 germline mutations in HNPCC families. To test this, we have inactivated the mouse genes Msh3 (formerly Rep3 ) and Msh6 (formerly Gtmbp). Msh6-deficient mice were prone to cancer; most animals developed lymphomas or epithelial tumours originating from the skin and uterus but only rarely from the intestine. Msh3 deficiency did not cause cancer predisposition, but in an Msh6 -deficient background, loss of Msh3 accelerated intestinal tumorigenesis. Lymphomagenesis was not affected. Furthermore, mismatch-directed anti-recombination and sensitivity to methylating agents required Msh2 and Msh6, but not Msh3. Thus, loss of MMR functions specific to Msh2/Msh6 is sufficient for lymphoma development in mice, whereas predisposition to intestinal cancer requires loss of function of both Msh2/Msh6 and Msh2/Msh3.
Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Reparación del ADN/genética , Proteínas de Unión al ADN/genética , Eliminación de Gen , Predisposición Genética a la Enfermedad/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos , Alelos , Animales , Disparidad de Par Base/genética , Muerte Celular/efectos de los fármacos , Neoplasias Colorrectales Hereditarias sin Poliposis/metabolismo , Neoplasias Colorrectales Hereditarias sin Poliposis/mortalidad , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/fisiología , Femenino , Incidencia , Masculino , Metilnitronitrosoguanidina/toxicidad , Ratones , Ratones Transgénicos , Proteína 3 Homóloga de MutS , Mutagénesis Insercional , Oligodesoxirribonucleótidos/genética , Oligodesoxirribonucleótidos/metabolismo , Células Madre/citología , Células Madre/efectos de los fármacos , Células Madre/metabolismo , Tasa de Supervivencia , Factores de TiempoRESUMEN
Hemizygosity for genes that are essential for DNA mismatch repair (MMR) was found to underlie cancer predisposition in hereditary nonpolypsis colorectal cancer (HNPCC). Loss of the wild-type allele generates a MMR-deficient cell compartment with a high propensity to oncogenic transformation. MMR deficiency not only accelerates spontaneous mutagenesis resulting from DNA replication errors, but also affects the cellular response to genotoxic agents. To study the consequences of MMR deficiency in vitro and to provide experimental access to HNPCC we have generated MMR-deficient cell lines and mice. The combination of MMR deficiency and exposure to genotoxic agents strongly accelerated lymphomagenesis.