Hijacked DNA repair proteins and unchained DNA polymerases.
Somatic hypermutation of immunoglobulin (Ig) genes occurs at a frequency that is a million times greater than the mutation in other genes. Mutations occur in variable genes to increase antibody affinity, and in switch regions before constant genes to cause switching from IgM to IgG. Hypermutation is initiated in activated B cells when the activation-induced deaminase protein deaminates cytosine in DNA to uracil. Uracils can be processed by either a mutagenic pathway to produce mutations or a non-mutagenic pathway to remove mutations. In the mutagenic pathway, we first studied the role of mismatch repair proteins, MSH2, MSH3, MSH6, PMS2 and MLH1, since they would recognize mismatches. The MSH2-MSH6 heterodimer is involved in hypermutation by binding to U:G and other mismatches generated during repair synthesis, but the other proteins are not necessary. Second, we analysed the role of low-fidelity DNA polymerases eta, iota and theta in synthesizing mutations, and conclude that polymerase eta is the dominant participant by generating mutations at A:T base pairs. In the non-mutagenic pathway, we examined the role of the Cockayne syndrome B protein that interacts with other repair proteins. Mice deficient in this protein had normal hypermutation and class switch recombination, showing that it is not involved.
Saribasak
Huseyin
H
Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
Rajagopal
Deepa
D
Maul
Robert W
RW
Gearhart
Patricia J
PJ
D000818:Animals; D000906:Antibodies / Q000235:genetics*; D020137:Base Pair Mismatch / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D051379:Mice; D008957:Models, Genetic; D051719:MutS DNA Mismatch-Binding Protein / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics* / Q000276:immunology; D014498:Uracil / Q000378:metabolism
D000906:Antibodies; D014498:Uracil; D004259:DNA-Directed DNA Polymerase; D051719:MutS DNA Mismatch-Binding Protein