Somatic Hypermutation: The Molecular Mechanisms Underlying the Production of Effective High-Affinity Antibodies. The Molecular Mechanisms Underlying the Production of Effective High-Affinity Antibodies.

V(D)J recombination produces a large repertoire of antibodies that can recognize diverse antigens. However, this repertoire is typically composed of antibodies that recognize their specific antigen with affinities that are too low to ensure the efficient clearance of infecting agents. To produce antibodies with higher affinity and sometimes changes in fine specificity, B-cells undergo a second antibody diversification process that in mice, humans, and many other species is called somatic hypermutation (SHM). Somatic hypermutation is initiated by and requires activation-induced cytidine deaminase, which converts pyrimidine (dC) to uridine (dU) on single-stranded DNA. The resulting dU:dG recruits noncanonical, error-prone forms of both base excision and mismatch repair to expand the process of SHM to include mutations in A:T as well as G:C base pairs. This ensemble of a highly mutagenic enzyme and subsequent error-prone repair results in the mutation of antibody V regions at about a million times higher frequency than occurs in other genes and is unique to antibody-forming B-cells.