Integrity of immunoglobulin variable regions is supported by GANP during AID-induced somatic hypermutation in germinal center B cells

Int Immunol. 2017 May 1;29(5):211-220. doi: 10.1093/intimm/dxx032.


Immunoglobulin affinity maturation depends on somatic hypermutation (SHM) in immunoglobulin variable (IgV) regions initiated by activation-induced cytidine deaminase (AID). AID induces transition mutations by C→U deamination on both strands, causing C:G→T:A. Error-prone repairs of U by base excision and mismatch repairs (MMRs) create transversion mutations at C/G and mutations at A/T sites. In Neuberger's model, it remained to be clarified how transition/transversion repair is regulated. We investigate the role of AID-interacting GANP (germinal center-associated nuclear protein) in the IgV SHM profile. GANP enhances transition mutation of the non-transcribed strand G and reduces mutation at A, restricted to GYW of the AID hotspot motif. It reduces DNA polymerase η hotspot mutations associated with MMRs followed by uracil-DNA glycosylase. Mutation comparison between IgV complementary and framework regions (FWRs) by Bayesian statistical estimation demonstrates that GANP supports the preservation of IgV FWR genomic sequences. GANP works to maintain antibody structure by reducing drastic changes in the IgV FWR in affinity maturation.

Keywords: DNA repair pathways; SHM; activation-induced cytidine deaminase; affinity maturation; antibody.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibody Affinity
  • B-Lymphocytes / immunology*
  • Bayes Theorem
  • Cells, Cultured
  • Cytidine Deaminase / metabolism
  • DNA Repair
  • Germinal Center / immunology*
  • Immunoglobulin Variable Region / genetics*
  • Immunoglobulin Variable Region / metabolism
  • Mice
  • Mice, Knockout
  • Mutation / genetics*
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Phosphoproteins / genetics*
  • Phosphoproteins / metabolism
  • Protein Conformation
  • Somatic Hypermutation, Immunoglobulin


  • GANP protein, mouse
  • Immunoglobulin Variable Region
  • Nuclear Proteins
  • Phosphoproteins
  • AICDA (activation-induced cytidine deaminase)
  • Cytidine Deaminase