Altered spectra of hypermutation in antibodies from mice deficient for the DNA mismatch repair protein PMS2.
Mutations are introduced into rearranged Ig variable genes at a frequency of 10(-2) mutations per base pair by an unknown mechanism. Assuming that DNA repair pathways generate or remove mutations, the frequency and pattern of mutation will be different in variable genes from mice defective in repair. Therefore, hypermutation was studied in mice deficient for either the DNA nucleotide excision repair gene Xpa or the mismatch repair gene Pms2. High levels of mutation were found in variable genes from XPA-deficient and PMS2-deficient mice, indicating that neither nucleotide excision repair nor mismatch repair pathways generate hypermutation. However, variable genes from PMS2-deficient mice had significantly more adjacent base substitutions than genes from wild-type or XPA-deficient mice. By using a biochemical assay, we confirmed that tandem mispairs were repaired by wild-type cells but not by Pms2(-/-) human or murine cells. The data indicate that tandem substitutions are produced by the hypermutation mechanism and then processed by a PMS2-dependent pathway.
Winter
D B
DB
Laboratory of Molecular Genetics, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
Phung
Q H
QH
Umar
A
A
Baker
S M
SM
Tarone
R E
RE
Tanaka
K
K
Liskay
R M
RM
Kunkel
T A
TA
Bohr
V A
VA
Gearhart
P J
PJ
D000251:Adenosine Triphosphatases; D000818:Animals; D000906:Antibodies / Q000235:genetics* / Q000276:immunology; D001483:Base Sequence; D004260:DNA Repair; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins; D005803:Genes, Immunoglobulin; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics / Q000276:immunology; D000070976:Mismatch Repair Endonuclease PMS2; D008969:Molecular Sequence Data; D009154:Mutation; D011506:Proteins / Q000235:genetics*
D000906:Antibodies; D004268:DNA-Binding Proteins; D007135:Immunoglobulin Variable Region; D011506:Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; C499533:Pms2 protein, mouse; D000070976:Mismatch Repair Endonuclease PMS2; D045643:DNA Repair Enzymes