Increased hypermutation at G and C nucleotides in immunoglobulin variable genes from mice deficient in the MSH2 mismatch repair protein.
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.
Phung
Q H
QH
Laboratory of Molecular Genetics, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
Winter
D B
DB
Cranston
A
A
Tarone
R E
RE
Bohr
V A
VA
Fishel
R
R
Gearhart
P J
PJ
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*
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