Different mutation signatures in DNA polymerase [eta]- and MSH6-deficient mice suggest separate roles in antibody diversification

Hypermutation in immunoglobulin genes produces a high frequency of substitutions of all four bases, which are likely generated by low-fidelity DNA polymerases. Indeed, humans deficient for DNA polymerase (pol) [eta] have decreased substitutions of A.T base pairs in variable and switch regions. To study the role of pol [eta] in a genetically tractable system, we created mice lacking pol [eta]. B cells from [Polh.sup.-/-] mice produced normal amounts of IgG, indicating that pol [eta] does not affect class switch recombination. Similar to their human counterparts, variable and switch regions from [Polh.sup.-/-] mice had fewer substitutions of A-T base pairs and correspondingly more mutations of C.G base pairs, which firmly establishes a central role for pol [eta] in hypermutation. Notably, the location and types of substitutions differ markedly from those in Msh[6.sup.-/-] clones, which also have fewer A x T mutations. The data suggest that pol [eta] preferentially synthesizes a repair patch on the nontranscribed strand, whereas MSH6 functions to generate the patch. class switch recombination | somatic hypermutation | low-fidelity DNA polymerase | mismatch repair