title: Increased hypermutation at G and C nucleotides in immunoglobulin variable genes from mice deficient in the MSH2 mismatch repair protein.
abstract: Rearranged immunoglobulin variable genes are extensively mutated after stimulation of B lymphocytes by antigen. Mutations are likely generated by an error-prone DNA polymerase, and the mismatch repair pathway may process the mispairs. To examine the role of the MSH2 mismatch repair protein in hypermutation, Msh2-/- mice were immunized with oxazolone, and B cells were analyzed for mutation in their VkappaOx1 light chain genes. The frequency of mutation in the repair-deficient mice was similar to that in Msh2+/+ mice, showing that MSH2-dependent mismatch repair does not cause hypermutation. However, there was a striking bias for mutations to occur at germline G and C nucleotides. The results suggest that the hypermutation pathway frequently mutates G.C pairs, and a MSH2-dependent pathway preferentially corrects mismatches at G and C.
authors.affiliation: Laboratory of Molecular Genetics, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
authors.forename: Q H
authors.initials: QH
authors.lastname: Phung
authors.forename: D B
authors.initials: DB
authors.lastname: Winter
authors.forename: A
authors.initials: A
authors.lastname: Cranston
authors.forename: R E
authors.initials: RE
authors.lastname: Tarone
authors.forename: V A
authors.initials: VA
authors.lastname: Bohr
authors.forename: R
authors.initials: R
authors.lastname: Fishel
authors.forename: P J
authors.initials: PJ
authors.lastname: Gearhart
mesh_terms: D000818:Animals; D001482:Base Composition; D001483:Base Sequence; D003596:Cytosine; D004260:DNA Repair; D004268:DNA-Binding Proteins; D017353:Gene Deletion; D015322:Gene Rearrangement, B-Lymphocyte; D006147:Guanine; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D007145:Immunoglobulin kappa-Chains / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D051718:MutS Homolog 2 Protein; D009154:Mutation; D009692:Nucleic Acid Heteroduplexes; D010081:Oxazolone / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D007135:Immunoglobulin Variable Region; D007145:Immunoglobulin kappa-Chains; D009692:Nucleic Acid Heteroduplexes; D011518:Proto-Oncogene Proteins; D010081:Oxazolone; D006147:Guanine; D003596:Cytosine; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein