{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T06:25:18Z","timestamp":1791267918243,"version":"4.1.0"},"reference-count":65,"publisher":"Rockefeller University Press","issue":"9","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2004,11,1]]},"abstract":"<jats:p>Immunoglobulin class switch recombination (Ig CSR) involves DNA double strand breaks (DSBs) at recombining switch regions and repair of these breaks by nonhomologous end-joining. Because the protein kinase ataxia telengiectasia (AT) mutated (ATM) plays a critical role in DSB repair and AT patients show abnormalities of Ig isotype expression, we assessed the role of ATM in CSR by examining ATM-deficient mice. In response to T cell\u2013dependent antigen (Ag), Atm\u2212\/\u2212 mice secreted substantially less Ag-specific IgA, IgG1, IgG2b, and IgG3, and less total IgE than Atm+\/+ controls. To determine whether Atm\u2212\/\u2212 B cells have an intrinsic defect in their ability to undergo CSR, we analyzed in vitro responses of purified B cells. Atm\u2212\/\u2212 cells secreted substantially less IgA, IgG1, IgG2a, IgG3, and IgE than wild-type (WT) controls in response to stimulation with lipopolysaccharide, CD40 ligand, or anti-IgD plus appropriate cytokines. Molecular analysis of in vitro responses indicated that WT and Atm\u2212\/\u2212 B cells produced equivalent amounts of germline IgG1 and IgE transcripts, whereas Atm\u2212\/\u2212 B cells produced markedly reduced productive IgG1 and IgE transcripts. The reduction in isotype switching by Atm\u2212\/\u2212 B cells occurs at the level of genomic DNA recombination as measured by digestion\u2013circularization PCR. Analysis of sequences at CSR sites indicated that there is greater microhomology at the \u03bc\u2013\u03b31 switch junctions in ATM B cells than in wild-type B cells, suggesting that ATM function affects the need or preference for sequence homology in the CSR process. These findings suggest a role of ATM in DNA DSB recognition and\/or repair during CSR.<\/jats:p>","DOI":"10.1084\/jem.20041074","type":"journal-article","created":{"date-parts":[[2004,10,26]],"date-time":"2004-10-26T00:14:00Z","timestamp":1098749640000},"page":"1111-1121","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":154,"title":["Immunoglobulin Class Switch Recombination Is Impaired in <i>Atm<\/i>-deficient Mice"],"prefix":"10.1084","volume":"200","author":[{"given":"Joanne M.","family":"Lumsden","sequence":"first","affiliation":[{"name":"1Experimental Immunology Branch, National Cancer Institute"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"McCarty","sequence":"additional","affiliation":[{"name":"2Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases (NIAID)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa K.","family":"Petiniot","sequence":"additional","affiliation":[{"name":"1Experimental Immunology Branch, National Cancer Institute"},{"name":"3Howard Hughes Medical Institute - National Institutes of Health Research Scholars Program, National Center for Human Genome Research"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rhuna","family":"Shen","sequence":"additional","affiliation":[{"name":"1Experimental Immunology Branch, National Cancer Institute"},{"name":"3Howard Hughes Medical Institute - National Institutes of Health Research Scholars Program, National Center for Human Genome Research"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carrolee","family":"Barlow","sequence":"additional","affiliation":[{"name":"4Genetic Disease Research Branch, National Center for Human Genome Research"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas A.","family":"Wynn","sequence":"additional","affiliation":[{"name":"5Laboratory of Parasitic Diseases, NIAID"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"III","given":"Herbert C.","family":"Morse","sequence":"additional","affiliation":[{"name":"2Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases (NIAID)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia J.","family":"Gearhart","sequence":"additional","affiliation":[{"name":"8Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, MD 21224"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Wynshaw-Boris","sequence":"additional","affiliation":[{"name":"4Genetic Disease Research Branch, National Center for Human Genome Research"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward E.","family":"Max","sequence":"additional","affiliation":[{"name":"6Center for Drugs Evaluation and Research, Food and Drug Administration"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J.","family":"Hodes","sequence":"additional","affiliation":[{"name":"1Experimental Immunology Branch, National Cancer Institute"},{"name":"7National Institute on Aging, National Institutes of Health (NIH), Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2004,10,25]]},"reference":[{"key":"2023072512512996000_BIB1","first-page":"99","volume":"418","year":"2002","journal-title":"Nature."},{"key":"2023072512512996000_BIB2","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/S0092-8674(00)00079-9","volume":"102","year":"2000","journal-title":"Cell."},{"key":"2023072512512996000_BIB3","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/S0092-8674(00)00078-7","volume":"102","year":"2000","journal-title":"Cell."},{"key":"2023072512512996000_BIB4","doi-asserted-by":"crossref","first-page":"2137","DOI":"10.1126\/science.1092481","volume":"302","year":"2003","journal-title":"Science."},{"key":"2023072512512996000_BIB5","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1126\/science.1098444","volume":"305","year":"2004","journal-title":"Science."},{"key":"2023072512512996000_BIB6","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/0092-8674(95)90463-8","volume":"82","year":"1995","journal-title":"Cell."},{"key":"2023072512512996000_BIB7","doi-asserted-by":"crossref","first-page":"1674","DOI":"10.1126\/science.281.5383.1674","volume":"281","year":"1998","journal-title":"Science."},{"key":"2023072512512996000_BIB8","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.1126\/science.281.5383.1677","volume":"281","year":"1998","journal-title":"Science."},{"key":"2023072512512996000_BIB9","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1038\/3882","volume":"20","year":"1998","journal-title":"Nat. Genet."},{"key":"2023072512512996000_BIB10","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1002\/bies.10101","volume":"24","year":"2002","journal-title":"Bioessays."},{"key":"2023072512512996000_BIB11","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1038\/35103059","volume":"2","year":"2001","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2023072512512996000_BIB12","doi-asserted-by":"crossref","first-page":"14973","DOI":"10.1073\/pnas.96.26.14973","volume":"96","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072512512996000_BIB13","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1101\/gad.886901","volume":"15","year":"2001","journal-title":"Genes Dev."},{"key":"2023072512512996000_BIB14","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1126\/science.286.5442.1162","volume":"286","year":"1999","journal-title":"Science."},{"key":"2023072512512996000_BIB15","doi-asserted-by":"crossref","first-page":"17276","DOI":"10.1074\/jbc.M011681200","volume":"276","year":"2001","journal-title":"J. Biol. Chem."},{"key":"2023072512512996000_BIB16","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1038\/35007091","volume":"404","year":"2000","journal-title":"Nature."},{"key":"2023072512512996000_BIB17","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1038\/75508","volume":"25","year":"2000","journal-title":"Nat. Genet."},{"key":"2023072512512996000_BIB18","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/35013089","volume":"405","year":"2000","journal-title":"Nature."},{"key":"2023072512512996000_BIB19","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/35043058","volume":"1","year":"2000","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2023072512512996000_BIB20","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1038\/nrc1011","volume":"3","year":"2003","journal-title":"Nat. Rev. Cancer."},{"key":"2023072512512996000_BIB21","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/nature01368","volume":"421","year":"2003","journal-title":"Nature."},{"key":"2023072512512996000_BIB22","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1126\/science.1091496","volume":"304","year":"2004","journal-title":"Science."},{"key":"2023072512512996000_BIB23","doi-asserted-by":"crossref","first-page":"38224","DOI":"10.1074\/jbc.M102986200","volume":"276","year":"2001","journal-title":"J. Biol. Chem."},{"key":"2023072512512996000_BIB24","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1101\/gad.956902","volume":"16","year":"2002","journal-title":"Genes Dev."},{"key":"2023072512512996000_BIB25","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1136\/jcp.54.7.512","volume":"54","year":"2001","journal-title":"J. Clin. Pathol."},{"key":"2023072512512996000_BIB26","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1182\/blood.V87.2.423.bloodjournal872423","volume":"87","year":"1996","journal-title":"Blood."},{"key":"2023072512512996000_BIB27","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/S0092-8674(00)80086-0","volume":"86","year":"1996","journal-title":"Cell."},{"key":"2023072512512996000_BIB28","doi-asserted-by":"crossref","first-page":"2411","DOI":"10.1101\/gad.10.19.2411","volume":"10","year":"1996","journal-title":"Genes Dev."},{"key":"2023072512512996000_BIB29","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/S0065-2776(08)60020-6","volume":"72","year":"1999","journal-title":"Adv. Immunol."},{"key":"2023072512512996000_BIB30","doi-asserted-by":"crossref","first-page":"1940","DOI":"10.1182\/blood.V96.5.1940","volume":"96","year":"2000","journal-title":"Blood."},{"key":"2023072512512996000_BIB31","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1172\/JCI110768","volume":"71","year":"1983","journal-title":"J. Clin. Invest."},{"key":"2023072512512996000_BIB32","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1097\/00005792-197207000-00002","volume":"51","year":"1972","journal-title":"Medicine (Baltimore)."},{"key":"2023072512512996000_BIB33","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1002\/1521-4141(200205)32:5<1300::AID-IMMU1300>3.0.CO;2-L","volume":"32","year":"2002","journal-title":"Eur. J. Immunol."},{"key":"2023072512512996000_BIB34","doi-asserted-by":"crossref","first-page":"3707","DOI":"10.4049\/jimmunol.170.7.3707","volume":"170","year":"2003","journal-title":"J. Immunol."},{"key":"2023072512512996000_BIB35","doi-asserted-by":"crossref","first-page":"3095","DOI":"10.1128\/MCB.19.4.3095","volume":"19","year":"1999","journal-title":"Mol. Cell. Biol."},{"key":"2023072512512996000_BIB36","doi-asserted-by":"crossref","first-page":"2369","DOI":"10.4049\/jimmunol.155.5.2369","volume":"155","year":"1995","journal-title":"J. Immunol."},{"key":"2023072512512996000_BIB37","doi-asserted-by":"crossref","first-page":"6953","DOI":"10.1073\/pnas.95.12.6953","volume":"95","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072512512996000_BIB38","doi-asserted-by":"crossref","first-page":"1767","DOI":"10.1084\/jem.20030569","volume":"197","year":"2003","journal-title":"J. Exp. Med."},{"key":"2023072512512996000_BIB39","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1056\/NEJM196908282810904","volume":"281","year":"1969","journal-title":"N. Engl. J. Med."},{"key":"2023072512512996000_BIB40","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1056\/NEJM198203043060905","volume":"306","year":"1982","journal-title":"N. Engl. J. Med."},{"key":"2023072512512996000_BIB41","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/0002-9343(66)90080-5","volume":"41","year":"1966","journal-title":"Am. J. Med."},{"key":"2023072512512996000_BIB42","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1007\/BF00915484","volume":"3","year":"1983","journal-title":"J. Clin. Immunol."},{"key":"2023072512512996000_BIB43","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.4049\/jimmunol.147.4.1163","volume":"147","year":"1991","journal-title":"J. Immunol."},{"key":"2023072512512996000_BIB44","first-page":"59","volume":"4","year":"1988","journal-title":"J. Mol. Cell. Immunol."},{"key":"2023072512512996000_BIB45","doi-asserted-by":"crossref","first-page":"6978","DOI":"10.1073\/pnas.89.15.6978","volume":"89","year":"1992","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072512512996000_BIB46","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1093\/emboj\/19.3.463","volume":"19","year":"2000","journal-title":"EMBO J."},{"key":"2023072512512996000_BIB47","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/S1074-7613(00)80258-7","volume":"5","year":"1996","journal-title":"Immunity."},{"key":"2023072512512996000_BIB48","doi-asserted-by":"crossref","first-page":"2081","DOI":"10.1084\/jem.187.12.2081","volume":"187","year":"1998","journal-title":"J. Exp. Med."},{"key":"2023072512512996000_BIB49","doi-asserted-by":"crossref","first-page":"2404","DOI":"10.1093\/emboj\/17.8.2404","volume":"17","year":"1998","journal-title":"EMBO J."},{"key":"2023072512512996000_BIB50","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1046\/j.1365-2249.2002.01830.x","volume":"129","year":"2002","journal-title":"Clin. Exp. Immunol."},{"key":"2023072512512996000_BIB51","doi-asserted-by":"crossref","first-page":"4082","DOI":"10.1182\/blood-2002-03-0976","volume":"100","year":"2002","journal-title":"Blood."},{"key":"2023072512512996000_BIB52","doi-asserted-by":"crossref","first-page":"9489","DOI":"10.1074\/jbc.272.14.9489","volume":"272","year":"1997","journal-title":"J. Biol. Chem."},{"key":"2023072512512996000_BIB53","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1002\/j.1460-2075.1986.tb04182.x","volume":"5","year":"1986","journal-title":"EMBO J."},{"key":"2023072512512996000_BIB54","doi-asserted-by":"crossref","first-page":"3259","DOI":"10.1002\/j.1460-2075.1986.tb04637.x","volume":"5","year":"1986","journal-title":"EMBO J."},{"key":"2023072512512996000_BIB55","doi-asserted-by":"crossref","first-page":"3223","DOI":"10.4049\/jimmunol.173.5.3223","volume":"173","year":"2004","journal-title":"J. Immunol."},{"key":"2023072512512996000_BIB56","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/S1074-7613(02)00306-0","volume":"16","year":"2002","journal-title":"Immunity."},{"key":"2023072512512996000_BIB57","first-page":"481","volume":"5","year":"2004","journal-title":"Nat. Immunol."},{"key":"2023072512512996000_BIB58","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1038\/414660a","volume":"414","year":"2001","journal-title":"Nature."},{"key":"2023072512512996000_BIB59","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1126\/science.1069398","volume":"296","year":"2002","journal-title":"Science."},{"key":"2023072512512996000_BIB60","first-page":"8586","volume":"63","year":"2003","journal-title":"Cancer Res."},{"key":"2023072512512996000_BIB61","doi-asserted-by":"crossref","first-page":"2708","DOI":"10.1074\/jbc.M007665200","volume":"276","year":"2001","journal-title":"J. Biol. Chem."},{"key":"2023072512512996000_BIB62","doi-asserted-by":"crossref","first-page":"1381","DOI":"10.1083\/jcb.151.7.1381","volume":"151","year":"2000","journal-title":"J. Cell Biol."},{"key":"2023072512512996000_BIB63","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1111\/j.1600-065X.1982.tb01056.x","volume":"67","year":"1982","journal-title":"Immunol. Rev."},{"key":"2023072512512996000_BIB64","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/0022-1759(87)90112-8","volume":"97","year":"1987","journal-title":"J. Immunol. Methods."},{"key":"2023072512512996000_BIB65","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.4049\/jimmunol.122.4.1203","volume":"122","year":"1979","journal-title":"J. Immunol."}],"container-title":["The Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/200\/9\/1111\/1716062\/jem20091111.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/200\/9\/1111\/1716062\/jem20091111.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T12:57:30Z","timestamp":1690289850000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/200\/9\/1111\/52443\/Immunoglobulin-Class-Switch-Recombination-Is"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2004,10,25]]},"references-count":65,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2004,11,1]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.20041074","relation":{},"ISSN":["1540-9538","0022-1007"],"issn-type":[{"value":"1540-9538","type":"electronic"},{"value":"0022-1007","type":"print"}],"subject":[],"published":{"date-parts":[[2004,10,25]]}}}