Somatic hypermutation in MutS homologue (MSH)3-, MSH6-, and MSH3/MSH6-deficient mice reveals a role for the MSH2-MSH6 heterodimer in modulating the base substitution pattern.
Although the primary function of the DNA mismatch repair (MMR) system is to identify and correct base mismatches that have been erroneously introduced during DNA replication, recent studies have further implicated several MMR components in somatic hypermutation of immunoglobulin (Ig) genes. We studied the immune response in mice deficient in MutS homologue (MSH)3 and MSH6, two mutually exclusive partners of MSH2 that have not been examined previously for their role in Ig hypermutation. In Msh6(-)/- and Msh3(-)/-/Msh6(-)/- mice, base substitutions are preferentially targeted to G and C nucleotides and to an RGYW hot spot, as has been shown previously in Msh2(-)/- mice. In contrast, Msh3(-)/- mice show no differences from their littermate controls. These findings indicate that the MSH2-MSH6 heterodimer, but not the MSH2-MSH3 complex, is responsible for modulating Ig hypermutation.
Wiesendanger
M
M
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Kneitz
B
B
Edelmann
W
W
Scharff
M D
MD
D000251:Adenosine Triphosphatases; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D001426:Bacterial Proteins / Q000235:genetics*; D020137:Base Pair Mismatch; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics*; D019281:Dimerization; D029968:Escherichia coli Proteins; D051379:Mice; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D051719:MutS DNA Mismatch-Binding Protein; D051718:MutS Homolog 2 Protein; D000074081:MutS Homolog 3 Protein; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000172:deficiency; D013154:Spleen / Q000276:immunology
D000251:Adenosine Triphosphatases; D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D029968:Escherichia coli Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D051719:MutS DNA Mismatch-Binding Protein; D051718:MutS Homolog 2 Protein; D000074081:MutS Homolog 3 Protein; D011518:Proto-Oncogene Proteins; C094443:G-T mismatch-binding protein; C078444:MSH3 protein, human; C102997:Msh6 protein, mouse; C497173:Msh2 protein, mouse; C497175:MutS protein, E coli; C421109:multidrug resistance-associated protein 1