The Function of AID in Somatic Mutation and Class Switch Recombination

Harvard University, Cambridge, Massachusetts, United States
Journal of Experimental Medicine (Impact Factor: 12.52). 06/2002; 195(9):F37-41. DOI: 10.1084/jem.20020380
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    • "Repair enzymes are not required for SHM, and their absence in repair-deficient mice has little effect on the frequency of SHM (Li et al., 2006); therefore, they are apparently not rate-limiting for mutagenesis. Although AID activity has been demonstrated in vitro, the function and substrate of AID in vivo is under discussion (Chua et al., 2002; Franklin and Blanden, 2006; Rogozin et al., 2004), and data indicate that the activity of AID in vivo is restricted drastically as compared to cell-free assays (Shen et al., 2006). Thus, in some respects the current model of SHM may reflect in vitro rather than in vivo conditions. "
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    ABSTRACT: The VH5 human antibody gene was analyzed using a computer program (mfg) which simulates transcription, to better understand transcription-driven mutagenesis events that occur during "phase 1" of somatic hypermutation. Results show that the great majority of mutations in the non-transcribed strand occur within loops of two predicted high-stability stem-loop structures, termed SLSs 14.9 and 13.9. In fact, 89% of the 2505 mutations reported are within the encoded complementarity-determining region (CDR) and occur in loops of these high-stability structures. In vitro studies were also done and verified the existence of SLS 14.9. Following the formation of SLSs 14.9 and 13.9, a sustained period of transcriptional activity occurs within a window size of 60-70 nucleotides. During this period, the stability of these two SLSs does not change, and may provide the substrate for base exchanges and mutagenesis. The data suggest that many mutable bases are exposed simultaneously at pause sites, allowing for coordinated mutagenesis.
    Full-text · Article · Nov 2011 · Molecular Immunology
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    • "(b) Immunoprecipitation analysis with anti-AID rabbit polyclonal antibody (see Section 2.5) shows a specific band (24-kDa) in whole-cell extracts obtained from a normal thymus, a lymphoma from lck/AID mouse (F.1 founder), an HTLV-I/AID mouse thymus (F.1 founder), a normal breast and mammary glands from three different MMTV/AID founders. Unniraman et al., 2004; Chua et al., 2002; Casali and Zan, 2004). Double strand breaks could be a prerequisite to persistent AID targeting to the nucleus and could facilitate its access to specific DNA regions. "
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    ABSTRACT: Activation-induced cytidine deaminase (AID), an enzyme with homology to members of the APOBEC family, is involved in somatic hypermutation (SHM) of immunoglobulin (Ig) genes, either by direct deamination of DNA or by an indirect action through its putative RNA editing activity. AID is able to mutate both Ig-like reporter constructs and selected non-Ig genes in normal B cells and in other cells when ectopically overexpressed in mammalian cells and transgenic mice. However, in spite of the fact that in these transgenic animals AID activity was driven by an ubiquitous promoter, only T lymphomas and lung adenomas occurred. In the present work, we constructed three sets of transgenic mice in which AID was under the control of lck, HTLV-I and MMTV promoters, respectively. The lck/AID mice developed thymic lymphomas with variable but high efficiency, while no tumor was detected in HTLV-I/AID mice after two years of monitoring. Four MMTV/AID founder mice died with an atypical clinical picture, although no mammary tumor was found. These findings suggest that additional factors, present in thymocytes but not in other tissues or in lymphoid cells at different stages of differentiation, are needed for AID to fully manifest its tumorigenic potential in mouse. Alternatively, the display of full AID mutagenic and transforming activity could be related to the existence of physiologic DSBs which occur in both thymocytes and switching B cells.
    Full-text · Article · Sep 2006 · Gene
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