DNA polymerase eta is a limiting factor for A:T mutations in Ig genes and contributes to antibody affinity maturation

Eur J Immunol. 2008 Oct;38(10):2796-805. doi: 10.1002/eji.200838502.


DNA polymerase eta (POLH) is required for the generation of A:T mutations during the somatic hypermutation of Ig genes in germinal center B cells. It remains unclear, however, whether POLH is a limiting factor for A:T mutations and how the absence of POLH might affect antibody affinity maturation. We found that the heterozygous Polh+/- mice exhibited a significant reduction in the frequency of A:T mutations in Ig genes, with each type of base substitutions at a level intermediate between the Polh+/+ and Polh(-/-) mice. These observations suggest that Polh is haplo-insufficient for the induction of A:T mutations in Ig genes. Intriguingly, there was also a reduction of C to T and G to A transitions in Polh+/- mice as compared with WT mice. Polh(-/-) mice produced decreased serum titers of high-affinity antibodies against a T-dependent antigen, which was associated with a significant reduction in the number of plasma cells secreting high-affinity antibodies. Analysis of the V region revealed that aa substitutions caused by A:T mutations were greatly reduced in Polh(-/-) mice. These results demonstrate that POLH is a limiting factor for A:T mutations and contributes to the efficient diversification of Ig genes and affinity maturation of antibodies.

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Antibodies / blood
  • Antibodies / immunology*
  • Antibody Affinity*
  • DNA-Directed DNA Polymerase / genetics
  • DNA-Directed DNA Polymerase / metabolism*
  • Gene Knockdown Techniques
  • Genes, Immunoglobulin*
  • Mice
  • Mice, Mutant Strains
  • Mutation*
  • Plasma Cells / immunology
  • Somatic Hypermutation, Immunoglobulin*


  • Antibodies
  • DNA-Directed DNA Polymerase
  • Rad30 protein