DNA polymerase eta is an A-T mutator in somatic hypermutation of immunoglobulin variable genes

To determine whether DNA polymerase eta plays a role in the hypermutation o f immunoglobulin variable genes, we examined the frequency and pattern of s ubstitutions in variable V(H)6 genes from the peripheral blood lymphocytes of three patients with xeroderma pigmentosum variant disease, whose polymer ase eta had genetic defects. The frequency of mutation was normal but the t ypes of base changes were different: there was a decrease in mutations at A and T and a concomitant rise in mutations at G and C. We propose that more than one polymerase contributes to hypermutation and that if one is absent , others compensate. The data indicate that polymerase eta is involved in g enerating errors that occur predominantly at A and T and that another polym erase(s) may generating errors that occur predominantly at A preferentially generate errors opposite G and C.