title: AID and Apobec3G haphazard deamination and mutational diversity.
abstract: Activation-induced deoxycytidine deaminase (AID) and Apobec 3G (Apo3G) cause mutational diversity by initiating mutations on regions of single-stranded (ss) DNA. Expressed in B cells, AID deaminates C → U in actively transcribed immunoglobulin (Ig) variable and switch regions to initiate the somatic hypermutation (SHM) and class switch recombination (CSR) that are essential for antibody diversity. Apo3G expressed in T cells catalyzes C deaminations on reverse transcribed cDNA causing HIV-1 retroviral inactivation. When operating properly, AID- and Apo3G-initiated mutations boost human fitness. Yet, both enzymes are potentially powerful somatic cell "mutators". Loss of regulated expression and proper genome targeting can cause human cancer. Here, we review well-established biological roles of AID and Apo3G. We provide a synopsis of AID partnering proteins during SHM and CSR, and describe how an Apo2 crystal structure provides "surrogate" insight for AID and Apo3G biochemical behavior. However, large gaps remain in our understanding of how dC deaminases search ssDNA to identify trinucleotide motifs to deaminate. We discuss two recent methods to analyze ssDNA scanning and deamination. Apo3G scanning and deamination is visualized in real-time using single-molecule FRET, and AID deamination efficiencies are determined with a random walk analysis. AID and Apo3G encounter many candidate deamination sites while scanning ssDNA. Generating mutational diversity is a principal aim of AID and an important ancillary property of Apo3G. Success seems likely to involve hit and miss deamination motif targeting, biased strongly toward miss.
authors.affiliation: Departments of Biological Sciences and Chemistry, Molecular and Computational Biology Section, University of Southern California, Los Angeles, CA 90089-2910, USA.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Jaszczur
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Bertram
authors.forename: Phuong
authors.initials: P
authors.lastname: Pham
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Scharff
authors.forename: Myron F
authors.initials: MF
authors.lastname: Goodman
mesh_terms: D000071480:APOBEC-3G Deaminase; D000916:Antibody Diversity; D001402:B-Lymphocytes / Q000378:metabolism*; D003564:Cytidine Deaminase / Q000235:genetics* / Q000378:metabolism*; D003641:Deamination; D016503:Drug Delivery Systems; D014644:Genetic Variation; D006801:Humans; D009154:Mutation; D057127:Single-Chain Antibodies / Q000235:genetics / Q000378:metabolism; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D057127:Single-Chain Antibodies; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase