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Double-Knockout Mice −/− Somatic Hypermutation and Class Switch Recombination in Msh6−/−Ung−/− Double-Knockout Mice This information is current as Hong Ming Shen, Atsushi Tanaka, Grazyna Bozek, Dan of October 2, 2021. Nicolae and Ursula Storb J Immunol 2006; 177:5386-5392; ; doi: 10.4049/jimmunol.177.8.5386 http://www.jimmunol.org/content/177/8/5386 Downloaded from References This article cites 44 articles, 20 of which you can access for free at: http://www.jimmunol.org/content/177/8/5386.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • 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 2, 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 © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Somatic Hypermutation and Class Switch Recombination in Msh6؊/؊Ung؊/؊ Double-Knockout Mice1 Hong Ming Shen,* Atsushi Tanaka,† Grazyna Bozek,* Dan Nicolae,‡ and Ursula Storb2*† Somatic hypermutation (SHM) and class switch recombination (CSR) are initiated by activation-induced cytosine deaminase (AID). The uracil, and potentially neighboring bases, are processed by error-prone base excision repair and mismatch repair. Deficiencies in Ung, Msh2, or Msh6 affect SHM and CSR. To determine whether Msh2/Msh6 complexes which recognize single- base mismatches and loops were the only mismatch-recognition complexes required for SHM and CSR, we analyzed these ;processes in Msh6؊/؊Ung؊/؊ mice. SHM and CSR were affected in the same degree and fashion as in Msh2؊/؊Ung؊/؊ mice mutations were mostly C,G transitions and CSR was greatly reduced, making Msh2/Msh3 contributions unlikely. Inactivating Ung alone reduced mutations from A and T, suggesting that, depending on the DNA sequence, varying proportions of A,T mutations ؊/؊ ؊/؊ ؅ ؅ arise by error-prone long-patch base excision repair. Further, in Msh6 Ung mice the 5 end and the 3 region of Ig genes Downloaded from was spared from mutations as in wild-type mice, confirming that AID does not act in these regions. Finally, because in the absence of both Ung and Msh6, transition mutations from C and G likely are “footprints” of AID, the data show that the activity of AID is restricted drastically in vivo compared with AID in cell-free assays. The Journal of Immunology, 2006, 177: 5386–5392. racil created by activation-induced cytosine deaminase (22). These findings showed that both BER and MMR are involved (AID)3 during somatic hypermutation (SHM) or class in SHM and CSR, and further, suggested that the two mechanisms http://www.jimmunol.org/ U switch recombination (CSR) can be eliminated in vari- may interact in the processing of the AID-created uracils (see ous ways, by direct copying during DNA replication, resulting in Discussion). C/G to T/A transitions, by base excision repair (BER) using Ung Msh2/Ung double-knockout mice produce essentially only C as the major uracil glycosylase, or by mismatch repair (MMR) and G transitions during SHM and have severely reduced CSR (reviewed in Refs. 1–4). In SHM, either the uracil alone and/or (23). We initiated crosses between Msh6Ϫ/Ϫ and UngϪ/Ϫ mice to neighboring bases can be altered, depending on whether BER or test whether MMR and BER are the major mechanisms of creating MMR are involved, and on the number of nucleotides excised and post-AID mutations from A and T, and transversions from C and the types of error-prone polymerases engaged. Inactivation of Ung G. We used Msh6 rather than Msh2 because the former, together results in an almost complete elimination of transversion mutations with Msh2 in a MutS␣ complex, is only involved in recognition of by guest on October 2, 2021 from C and G, while the frequency of mutations from C and G single base-pair mismatches and single base loops, whereas Msh2, overall is not altered and mutations from A and T are still rela- in combination with Msh3 (MutS␤), is also involved in recogniz- Ϫ/Ϫ tively frequent (3, 4). Ung mice also are defective in CSR (5). ing larger loops (24). AID creates single base U/G mismatches; Inactivation of the MMR recognition proteins Msh2 or Msh6 re- larger mismatches and unpaired loops are not direct consequences duces overall mutations and greatly reduces mutations from A or of AID deamination, although loops may arise during CSR in R- Ϫ/Ϫ Ϫ/Ϫ T (6–11). CSR is also diminished in Msh2 and Msh6 mice looped switch regions, and potentially during SHM if AID deami- (2, 6, 7, 12–14). Genes that encode proteins involved in postmis- nates two or more consecutive Cs or if error-prone repair causes a match recognition functions of MMR have also been shown to be mismatch of more than one nucleotide. A potentially different role involved in SHM and CSR. Mice deficient in the MutL homologs of the mismatch repair complex MutS␤ (Msh2/Msh3) compared Mlh1 and Pms2 have altered SHM and CSR patterns (13–20). with MutS␣ (Msh2/Msh6) was suggested, because the pattern of Exonuclease 1-mutant mice have altered SHM and reduced CSR switch joints appeared to differ in Msh2Ϫ/Ϫ and Msh6Ϫ/Ϫ mice (21). Interestingly, mice deficient in Mlh3 have increased SHM, (12). Recently, it was suggested that Msh6 may serve as a scaffold suggesting that Mlh3 normally reduces the SHM mutation load in SHM (25). The Msh6Ϫ/ϪUngϪ/Ϫ mice were also important to further study whether the sparing of the very 5Ј end and the C region of Ig genes *Department of Molecular Genetic and Cell Biology, †Committee on Immunology, during SHM was indeed due to lack of AID access/activity in these ‡ and Department of Statistics, University of Chicago, Chicago, IL 60637 regions. We found previously that the lack of mutations in the very Received for publication May 23, 2006. Accepted for publication July 20, 2006. 5Ј and 3Ј regions of Ig genes was as severe in UngϪ/Ϫ mice as in The costs of publication of this article were defrayed in part by the payment of page wild-type mice and concluded that AID did not function in these charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. regions (26). There remained the possibility that AID-created ura- Ј Ј Ϫ/Ϫ 1 This work was supported by National Institutes of Health Grants AI47380 and cils were present in the 5 and 3 regions of Ung mice, but that AI053130. U/Gs in these flanking regions were repaired error-free by MMR 2 Address correspondence and reprint requests to Dr. Ursula Storb, Department of that proceeded without mistakes, as MMR would elsewhere in the Molecular Genetics and Cell Biology, University of Chicago, 920 East 58th Street, genome. In that case, uracils in the 5Ј and 3Ј ends could have been Chicago, IL 60637. E-mail address: [email protected] faithfully repaired to cytosines by MMR. Elimination of both sin- 3 Abbreviations used in this paper: AID, activation-induced cytosine deaminase; SHM, somatic hypermutation; CSR, class switch recombination; BER, base excision gle-mismatch MMR and Ung likely reveals whether error-free repair; MMR, mismatch repair; SRBC, sheep RBC; PNA, peanut lectin agglutinin. copying of uracils occurs in Ig gene SHM. Copyright © 2006 by The American Association of Immunologists, Inc. 0022-1767/06/$02.00 The Journal of Immunology 5387 Materials and Methods ates). Briefly, 5 ␮g of capture Ab was added to each well in an ELISA Mice plate, and the plate was incubated overnight at 4°C. After rinsing the plate three times with PBS containing 0.05% Tween 20 to remove the extra UngϪ/Ϫ mice were a gift of D. Barnes and T. Lindahl (Imperial Cancer capture Ab, the wells were blocked with 1% BSA. The diluted serum Research Fund, Clare Hall Laboratories, South Mimms, U.K.), and were samples containing Igs of interest were then added to the wells, and the further bred in our mouse facility on a C57BL/6 background. A male ELISA plate was incubated overnight at 4°C. Unbound serum proteins Msh6ϩ/Ϫ mouse was obtained from the Mouse Repository at the National were rinsed out with PBS containing 0.05% Tween 20 before various Abs Cancer Institute (Rockville, MD); the latter mice were originally donated by anti-Ig C regions conjugated with alkaline phosphatase were added. The W. Edelmann (Albert Einstein College of Medicine, Bronx, NY). Both plate was incubated at room temperature on a shaker for 1 h. Unbound Abs UngϪ/Ϫ and Msh6ϩ/Ϫ mice had a C57BL/6 ϫ 129 background. The mice were removed by rinsing the plate five times with PBS containing 0.05% were maintained according to National Institutes of Health instructions. Tween 20. The substrate ( p-nitrophenyl phosphate) was added to the wells ϩ/Ϫ ϩ/Ϫ Ϫ/Ϫ (Ung Msh6 )F1 mice were acquired by crossing Ung mice with the and the OD was read at 405 nm in the Synergy HT reader (Bio-Tek In- Msh6ϩ/Ϫ mouse. Offspring were further crossed twice to generate UngϪ/Ϫ struments) at various time periods.
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