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An Evolutionary View of the Mechanism for Immune and Genome Diversity Lucia Kato, Andre Stanlie, Nasim A. Begum, Maki Kobayashi, Masatoshi Aida and Tasuku Honjo This information is current as of October 1, 2021. J Immunol 2012; 188:3559-3566; ; doi: 10.4049/jimmunol.1102397 http://www.jimmunol.org/content/188/8/3559 Downloaded from References This article cites 65 articles, 30 of which you can access for free at: http://www.jimmunol.org/content/188/8/3559.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 1, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: 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 © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. An Evolutionary View of the Mechanism for Immune and Genome Diversity Lucia Kato, Andre Stanlie, Nasim A. Begum, Maki Kobayashi, Masatoshi Aida, and Tasuku Honjo An ortholog of activation-induced cytidine deaminase Another mechanism for genome diversification in eukar- (AID) was, evolutionarily, the first enzyme to generate yotes is mediated by meiotic recombination, which occurs in acquired immune diversity by catalyzing gene conversion gametogenesis. Most of the mechanisms and molecules in and probably somatic hypermutation (SHM). AID be- meiotic recombination are highly conserved from yeast to gan to mediate class switch recombination (CSR) only humans (6). Meiotic recombination might have contributed after the evolution of frogs. Recent studies revealed that to enhance the scrambling of mutations and facilitate Dar- winian selection. the mechanisms for generating immune and genetic di- Downloaded from versity share several critical features. Meiotic recombina- Vertebrate immune diversity is mediated by two types of tion, V(D)J recombination, CSR, and SHM all require DNA-alteration mechanisms: V(D)J recombination by RAG1/ H3K4 trimethyl histone modification to specify the tar- RAG2 and somatic hypermutation (SHM)/class switch re- get DNA. Genetic instability related to dinucleotide or combination (CSR)/gene conversion (GC) by activation- induced cytidine deaminase (AID) (7, 8). Acquired immune triplet repeats depends on DNA cleavage by topoisom- diversity appears to have evolved at a very early stage of ver- http://www.jimmunol.org/ erase 1, which also initiates DNA cleavage in both tebrate evolution, because an AID ortholog, Petromyzon SHM and CSR. These similarities suggest that AID marinus cytidine deaminase (PmCDA), was identified in hijacked the basic mechanism for genome instability a lamprey, P. marinus (9). In lampreys, two AID family when AID evolved in jawless fish. Thus, the risk of in- members, PmCDA1 and PmCDA2, are expressed differen- troducing genome instability into nonimmunoglobulin tially in two types of Ag-recognizing cells that correspond to loci is unavoidable but tolerable compared with the ad- T cell and B cell precursors, which express variable lymphocyte vantage conferred on the host of being protected against receptors (VLR) A and VLRB, respectively. RAG1/RAG2 and pathogens by the enormous Ig diversification. The V(D)J recombination appeared later in vertebrate evolution. Journal of Immunology, 2012, 188: 3559–3566. Given their gene structure, which lacks introns, and their by guest on October 1, 2021 recognition of a specific DNA sequence, RAG1/RAG2 may have been introduced as retrotransposons, as the result of an enome stability is critical for the survival of living infection (10). Thus, it is likely that the evolution of AID was organisms. However, complete genome stability would the origin of acquired immune diversity. G have prevented the evolution of organisms, as well as Recent findings suggest that the SHM and CSR mediated by novel biological activities. Thus, an appropriate balance between AID have mechanisms similar to those of meiotic recombi- genome stability and instability has been maintained during nation, TAM, and triplet contraction/expansion (3–5, 11–15). evolution. There are several endogenous mechanisms in addition Some of these processes are shared by V(D)J recombination to exogenous genome-altering mechanisms, such as viral infec- (8). In this review, we attempt to discuss, from an evolution, irradiation, and DNA-damaging chemicals. It is well tionary point of view, the mechanisms for acquired immune established that high-frequency transcription enhances muta- diversity and classical genetic alterations and propose that genesis; this phenomenon is called transcription-associated mu- AID adopted the basic mechanism of genome instability to tation (TAM) (1). In addition, in the many triplet-associated generate immune diversity in lymphocytes. diseases, such as Huntington’s disease (2), the triplets are usually located within the transcribed region of genes, and the triplet General genome diversity repeats are either expanded or contracted in somatic cells. Recent Genome instability. Mutations form the basis of genetic diver- studies showed that topoisomerase 1 (Top1) is involved in both sity and instability. Living organisms have several intrinsic TAM and the triplet contraction/expansion (3–5). mechanisms for inducing mutations in DNA, in addition to Department of Immunology and Genomic Medicine, Graduate School of Medicine, Yoshida Sakyo-ku, Kyoto 606-8501, Japan. E-mail address: [email protected]. Kyoto University, Kyoto 606-8501, Japan ac.jp. Received for publication December 27, 2011. Accepted for publication February 9, Abbreviations used in this article: AID, activation-induced cytidine deaminase; CSR, 2012. class switch recombination; GC, gene conversion; LRR, leucine-rich repeat; MRN, Mre11/Rad50/NBS1 complex; PmCDA, Petromyzon marinus cytidine deaminase; SHM, This work was supported by Grant-in-Aid for Specially Promoted Research 17002015 somatic hypermutation; TAM, transcription-associated mutation; Top1, topoisomerase 1; from the Ministry of Education, Culture, Sports, Science and Technology of Japan. UNG, uracil-DNA glycosylase; VLR, variable lymphocyte receptor. Address correspondence and reprint requests to Prof. Tasuku Honjo, Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Copyright Ó 2012 by The American Association of Immunologists, Inc. 0022-1767/12/$16.00 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1102397 3560 BRIEF REVIEWS: SIMILARITIES BETWEEN IMMUNE DIVERSITY AND GENOME INSTABILITY errors that occur during DNA replication. The best-known example is TAM, which has been observed in a wide range of organisms, including Escherichia coli, yeast, and mammals (1). Highly active transcription increases the frequency of various types of mutations: base replacement, deletion, and recombination. Among these, 2–5-bp deletions were recently shown to be catalyzed by Top1 (4, 5). The 2–5-bp deletion type of TAM involves mutation hotspots containing di- or trinucleotide repeats. Efficient transcription often induces a loosening of the helical structure, resulting in the creation of excessively negative super- coiling behind the transcription machinery. Top1 is the enzyme that corrects this excessive DNA superhelix (Fig. 1A, 1B). Top1 nicks the DNA, forms a transient covalent bond with the DNA through its tyrosine residue, rotates the DNA around the helix, and then religates the cleaved ends; this set of actions can result in an increase or decrease of the superhelix (16). Notably, the active transcription of repeat sequences is predicted to form non-B DNA structures (17, Downloaded from 18). When the DNA has aberrant structures like non-B DNA, rotation around the helix may be inhibited; thus, the cleavage by Top1 may be irreversible and trigger genome instability (Fig. 1C) (4, 5, 17). Another well-known example of genome instability is associated with triplet diseases, such as Huntington’s disease, http://www.jimmunol.org/ Fragile X syndrome, and myotonic dystrophy, in which triplet repeats composed of CAG, CGG, CTG, and others increase or decrease in copy number (2). These triplet repeats are FIGURE 1. Molecular mechanism for transcription-induced DNA cleavage usually located within a transcription unit and are probably by Top1. (A) Transcription creates positive and negative supercoils in the prone to form non-B structures similarly to TAM (18). Re- front and rear, respectively, of the transcriptional machinery. This excessive supercoil has to be corrected by Top1. Otherwise, non-B DNA structures cently, triplet repeat contraction was shown to be caused by tend to form under the negative supercoil condition in areas where repetitive Top1 (3). Taken together, these findings suggest that TAM sequences or inverted repeats are abundant. (B) Excessive supercoil is cor- and triplet diseases probably arise by a similar molecular rected by Top1. Top1 introduces a nick and covalently associates with the 39 by guest on October 1, 2021 mechanism, as follows: non-B

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