title: Antibody diversification caused by disrupted mismatch repair and promiscuous DNA polymerases.
abstract: The enzyme activation-induced deaminase (AID) targets the immunoglobulin loci in activated B cells and creates DNA mutations in the antigen-binding variable region and DNA breaks in the switch region through processes known, respectively, as somatic hypermutation and class switch recombination. AID deaminates cytosine to uracil in DNA to create a U:G mismatch. During somatic hypermutation, the MutSα complex binds to the mismatch, and the error-prone DNA polymerase η generates mutations at A and T bases. During class switch recombination, both MutSα and MutLα complexes bind to the mismatch, resulting in double-strand break formation and end-joining. This review is centered on the mechanisms of how the MMR pathway is commandeered by B cells to generate antibody diversity.
authors.affiliation: Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Zanotti
authors.affiliation: Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. Electronic address: gearhartp@mail.nih.gov.
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Gearhart
mesh_terms: D000818:Animals; D000906:Antibodies / Q000378:metabolism*; D001483:Base Sequence; D003564:Cytidine Deaminase / Q000378:metabolism*; D053843:DNA Mismatch Repair; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D000906:Antibodies; D004259:DNA-Directed DNA Polymerase; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase
keywords: Activation-induced deaminase; Class switch recombination; DNA polymerase η; Mismatch repair; Somatic hypermutation