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

Keiji Masuda, Rika Ouchida, Masayuki Yokoi, Fumio Hanaoka, Takachika Azuma, Ji Yang Wang

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

DNA polymerase η (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/- 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 mice. 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.

Original languageEnglish
Pages (from-to)2796-2805
Number of pages10
JournalEuropean Journal of Immunology
Volume38
Issue number10
DOIs
Publication statusPublished - Dec 1 2008
Externally publishedYes

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All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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