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Deamination Advantages and Disadvantages of Cytidine Advantages and Disadvantages of Cytidine Deamination Marilia Cascalho This information is current as J Immunol 2004; 172:6513-6518; ; of October 2, 2021. doi: 10.4049/jimmunol.172.11.6513 http://www.jimmunol.org/content/172/11/6513 References This article cites 80 articles, 34 of which you can access for free at: Downloaded from http://www.jimmunol.org/content/172/11/6513.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision http://www.jimmunol.org/ • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: by guest on October 2, 2021 http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2004 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. THE JOURNAL OF IMMUNOLOGY BRIEF REVIEWS Advantages and Disadvantages of Cytidine Deamination1 Marilia Cascalho2 Cytidine deamination of nucleic acids underlies diversifi- and secreted in the triglyceride-rich chylomicrons that carry di- cation of Ig genes and inhibition of retroviral infection, etary fat (6). A nonedited apo B mRNA is produced in the liver, and thus, it would appear to be vital to host defense. The where it generates apo B-100, which is a component of the very- host defense properties of cytidine deamination require low-density and low-density lipoproteins (6) that mediate the two distinct but homologous cytidine deaminases—acti- transport of endogenously produced lipids. vation-induced cytidine deaminase and apolipoprotein B- Cytidine deamination and diversification of the Ig genes editing cytidine deaminase, subunit 3G. Although cyti- Activation-induced cytidine deaminase (AID) was discovered dine deamination has clear benefits, it might well have by Muramatsu et al. (7) as an APOBEC1 homolog with cyti- Downloaded from biological costs. Uncontrolled cytidine deamination might dine deaminase properties in stimulated B cell lines. Mura- generate misfolded polypeptides, dominant-negative pro- matsu et al. (8) showed that AID is necessary for somatic hy- Ϫ Ϫ teins, or mutations in tumor suppressor genes, and thus permutation and class switch recombination, because AID / contribute to tumor formation. How cytidine deaminases B lymphocytes do not undergo class switch recombination and target a given nucleic acid substrate at specific sequences is fail to accumulate mutations upon Ag stimulation. Mutations in the human AID gene causing lack of function underlie one not understood, and what protects cells from uncontrolled http://www.jimmunol.org/ mutagenesis is not known. In this paper, I shall review the type of hyper-IgM syndrome. In this syndrome, B cells fail to functions and regulation of activation-induced cytidine switch from IgM to other isotypes, and somatic hypermutation deaminase and apolipoprotein B-editing cytidine deami- of the Ig V regions does not occur (9). This syndrome seemingly nase, subunit 3G, and speculate about the basis for site connects AID with Ig isotype class switch and somatic hyper- specificity vis-a`-vis generalized mutagenesis. The Jour- mutation. Arakawa et al. (10) demonstrated that AID is also nal of Immunology, 2004, 172: 6513–6518. required for Ig gene conversion in chicken B cell lines. Thus, AID participates in three different processes that contribute to the diversification of Abs: somatic hypermutation, isotype class ytidine deamination was discovered as a mechanism of by guest on October 2, 2021 switch recombination, and gene conversion. editing mRNA transcripts in eukaryotes (RNA edit- Somatic hypermutation involves the introduction of non- C ing) (1, 2). RNA editing modifies transcripts in many templated mutations in the V region of the Ig genes at a rate that organisms and thus contributes to expanding the number of is one million times greater than the basal rate (11); gene con- gene products without the generation of new genes. Deamina- version consists of the introduction of templated mutations in tion of cytidine (C) to uridine (U) in RNA may create start the V region of Ig genes by copying into the active gene nucle- codons, thus originating new open reading frames; it may in- otide stretches from existent template sequences that remain troduce premature stop codons, producing truncated forms of unaltered (12). Class switch recombination changes the C re- proteins; it may open interrupted reading frames, giving rise to gion of Ig H chain genes and thus the effector functions of Abs novel proteins; or it may modify base pairing in RNA molecules (13). Class switch recombination consists of the ligation of to create alternative secondary structures that could alter RNA the Ig H chain V region to C region exons downstream of C␮ stability. and C␦ following looping out and deleting the intervening One well-studied type of C-to-U RNA editing is catalyzed by DNA (13). the apolipoprotein (apo)3 B RNA-editing cytidine deaminase Given the diverse impact of AID on Ig genes, the question has (APOBEC)1. APOBEC1 edits apo B mRNA at a specific site emerged of whether AID is an RNA-editing enzyme (8) like by deaminating cytidine-6666 to uridine, thus converting a glu- APOBEC1, or whether it might directly deaminate dC to dU in tamine codon 2153 (CAA) into a premature stop codon the DNA (14). The discovery that AID mutates dC residues in (UAA), producing a truncated form of apo B (apo B-48) (1, Escherichia coli DNA (14) and in ssDNA in vitro (15–17) sug- 3–5). The truncated apo B is synthesized in the small intestine gests that AID may mutate ssDNA and not RNA in B cells. Faili Transplantation Biology, and Departments of Immunology, Surgery, and Pediatrics, 2 Address correspondence and reprint requests to Dr. Marilia Cascalho, Transplantation Mayo Clinic, Rochester, MN 55905 Biology, Mayo Clinic, 200 First Street SW, Medical Sciences 2-113, Rochester, MN 55905. E-mail address: [email protected] Received for publication March 11, 2004. Accepted for publication April 9, 2004. 3 Abbreviations used in this paper: apo, apolipoprotein; APOBEC, apo B RNA-editing The costs of publication of this article were defrayed in part by the payment of page charges. cytidine deaminase; AID, activation-induced cytidine deaminase; UNG, uracil DNA gly- This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. cosylase; Vif, viral infectivity factor; Id, inhibitor of differentiation. Section 1734 solely to indicate this fact. 1 Work in the author’s laboratory is supported by Grant AI 48602 from the National In- stitutes of Health. Copyright © 2003 by The American Association of Immunologists, Inc. 0022-1767/03/$02.00 6514 BRIEF REVIEWS: ADVANTAGES AND DISADVANTAGES OF CYTIDINE DEAMINATION et al. (17) found mutations in one DNA strand, in the absence tion of which was overcome by HIV (viral infectivity factor of de novo RNA synthesis, suggesting that AID might induce (Vif)). APOBEC3G deaminates dC to dU in the retroviral mi- mutagenesis directly without RNA editing. Bransteitter et al. nus strand following reverse transcription (cDNA) (37–39). (15) suggested that RNA molecules inhibit AID function in APOBEC3G mutates retroviral cDNA by creating uracil bases vitro, because the addition of RNase greatly enhances deamina- in the place of cytidines. Uracil-containing cDNA may be tion of dC residues in ssDNA molecules. However, RNA may cleaved by UNG, causing degradation of viral cDNA, defective still be required for AID function. Thus, Chaudhuri et al. (18) production of early gene products, and impaired integration of found that AID function requires transcription and suggested provirus in the host genome, thus decreasing virus infectivity (J. that transcription may generate RNA-DNA hybrids and a sec- Gonc¸alves, unpublished observations) (40, 41). APOBEC3G ondary structure recognized by the enzyme. Alternatively, AID may also generate viral variants and in this way help viruses es- may associate with the transcription machinery itself, which cape the immune response of the host. The deaminase function could target AID to transcribed genes (19, 20). of APOBEC3G confers protection against retroviruses, because How cytidine deamination by AID promotes biochemically substitutions in the deaminase domain of APOBEC3G (defined distinct mechanisms of nucleic acid modification in B cells is by analogy with AID and APOBEC1) (Fig. 1) cause substantial incompletely understood. Petersen-Mahrt et al. (14) proposed increases in viral infectivity coincident with decreased dC-dT that cytidine deamination by AID introduces a U opposite to a mutations and decreased activity in free nucleotides (37, 38). G in DNA, thus creating a mismatch. If the mismatch is not repaired, then one of the daughter cells will have a C/G to T/A The mechanism of cytidine deamination transition, because U does not pair with G. In the absence of Downloaded from repair, each cytidine deamination event would yield a transition Cytidine deamination by APOBEC1 begins with activation of in half of the cellular progeny, provided that the
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