{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T05:36:25Z","timestamp":1775280985246,"version":"3.50.1"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2019,3,16]],"date-time":"2019-03-16T00:00:00Z","timestamp":1552694400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"JSPS KAKENHI Grant-in-Aid for Scientific Research","award":["15H05784"],"award-info":[{"award-number":["15H05784"]}]},{"name":"Grant-in-Aid for Scientific Research","award":["16K07251"],"award-info":[{"award-number":["16K07251"]}]},{"name":"Ono Pharmaceutical Company"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,7,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Activation-induced cytidine deaminase (AID) initiates DNA breakage in the variable (V) and switch (S) regions of the immunoglobulin gene, which results in somatic hypermutation (SHM) and class switch recombination (CSR), respectively. Apurinic\/apyrimidinic endonuclease 1 (APE1) has been shown to be important for CSR, and is supposed to cleave at abasic sites when AID-dependently deaminated cytidine is removed by uracil DNA glycosylase. However, APE1 is unexpectedly dispensable for SHM in the S region and translocation between immunoglobulin heavy chain (IgH) and c-myc genes in the mouse B lymphoma cell line, CH12F3-2A. This suggested that APE1 is not involved in AID-dependent DNA breakage, but rather, in DNA repair. In order to investigate detailed molecular mechanisms underlying APE1\u2019s involvement in CSR and SHM, we measured apurinic\/apyrimidinic (AP) sites via aldehyde reactive probe labeling. Results indicated that the frequencies of AP sites in the S regions were not different between APE1\u2212\/\u2212\/\u2212CH12F3-2A and wild-type CH12F3-2A cells. To carry out similar experiments in SHM of the V region, we generated an APE1 knockout (APE1\u2212\/\u2212) human Burkitt\u2019s lymphoma cell line, and compared SHM between APE1-proficient and -deficient BL2 lymphoma cells. SHM frequencies in the V regions of APE1\u2212\/\u2212BL2 and APE1-proficient cells were also similar. Taken together, we showed that AID does not induce AP sites in the S region of the IgH gene, and that APE1 is not necessary for SHM in the V and S regions; however, it is required for DNA repair following DNA breakage in CSR.<\/jats:p>","DOI":"10.1093\/intimm\/dxz028","type":"journal-article","created":{"date-parts":[[2019,3,14]],"date-time":"2019-03-14T14:58:51Z","timestamp":1552575531000},"page":"543-554","source":"Crossref","is-referenced-by-count":7,"title":["Apurinic\/apyrimidinic endonuclease 1 (APE1) is dispensable for activation-induced cytidine deaminase (AID)-dependent somatic hypermutation in the immunoglobulin gene"],"prefix":"10.1093","volume":"31","author":[{"given":"Helena","family":"Islam","sequence":"first","affiliation":[{"name":"Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Yoshida-Konoe cho, Sakyo-ku, Kyoto, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maki","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Yoshida-Konoe cho, Sakyo-ku, Kyoto, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tasuku","family":"Honjo","sequence":"additional","affiliation":[{"name":"Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Yoshida-Konoe cho, Sakyo-ku, Kyoto, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2019,3,16]]},"reference":[{"key":"2022071822160585500_CIT0001","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/S0092-8674(00)00078-7","article-title":"Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme","volume":"102","author":"Muramatsu","year":"2000","journal-title":"Cell"},{"key":"2022071822160585500_CIT0002","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/S0092-8674(00)00079-9","article-title":"Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the hyper-IgM syndrome (HIGM2)","volume":"102","author":"Revy","year":"2000","journal-title":"Cell"},{"key":"2022071822160585500_CIT0003","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1126\/science.1067308","article-title":"Requirement of the activation-induced deaminase (AID) gene for immunoglobulin gene conversion","volume":"295","author":"Arakawa","year":"2002","journal-title":"Science"},{"key":"2022071822160585500_CIT0004","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/B978-012053641-2\/50021-6","article-title":"Chapter 20\u2014molecular mechanism of class switch recombination","volume-title":"Molecular Biology of B Cells","author":"Stavnezer","year":"2004"},{"key":"2022071822160585500_CIT0005","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/j.cell.2004.08.006","article-title":"AID is required for c-myc\/IgH chromosome translocations in vivo","volume":"118","author":"Ramiro","year":"2004","journal-title":"Cell"},{"key":"2022071822160585500_CIT0006","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1038\/ni1086","article-title":"Separate domains of AID are required for somatic hypermutation and class-switch recombination","volume":"5","author":"Shinkura","year":"2004","journal-title":"Nat. Immunol."},{"key":"2022071822160585500_CIT0007","doi-asserted-by":"crossref","first-page":"2758","DOI":"10.1073\/pnas.0813253106","article-title":"The C-terminal region of activation-induced cytidine deaminase is responsible for a recombination function other than DNA cleavage in class switch recombination","volume":"106","author":"Doi","year":"2009","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2022071822160585500_CIT0008","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1038\/ni964","article-title":"AID mutant analyses indicate requirement for class-switch-specific cofactors","volume":"4","author":"Ta","year":"2003","journal-title":"Nat. Immunol."},{"key":"2022071822160585500_CIT0009","doi-asserted-by":"crossref","first-page":"2253","DOI":"10.1073\/pnas.1324057111","article-title":"C-terminal region of activation-induced cytidine deaminase (AID) is required for efficient class switch recombination and gene conversion","volume":"111","author":"Sabouri","year":"2014","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2022071822160585500_CIT0010","doi-asserted-by":"crossref","first-page":"13860","DOI":"10.1073\/pnas.241524898","article-title":"Variable deletion and duplication at recombination junction ends: implication for staggered double-strand cleavage in class-switch recombination","volume":"98","author":"Chen","year":"2001","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2022071822160585500_CIT0011","first-page":"305","article-title":"Chapter 18\u2014molecular mechanisms of AID function","volume-title":"Molecular Biology of B Cells","author":"Begum","year":"2015","edition":"2"},{"key":"2022071822160585500_CIT0012","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1146\/annurev.immunol.20.090501.112049","article-title":"Molecular mechanism of class switch recombination: linkage with somatic hypermutation","volume":"20","author":"Honjo","year":"2002","journal-title":"Annu. Rev. Immunol."},{"key":"2022071822160585500_CIT0013","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1084\/jem.20080669","article-title":"Pol zeta ablation in B cells impairs the germinal center reaction, class switch recombination, DNA break repair, and genome stability","volume":"206","author":"Schenten","year":"2009","journal-title":"J. Exp. Med."},{"key":"2022071822160585500_CIT0014","doi-asserted-by":"crossref","first-page":"5528","DOI":"10.4049\/jimmunol.1102629","article-title":"Altered Ig hypermutation pattern and frequency in complementary mouse models of DNA polymerase \u03b6 activity","volume":"188","author":"Daly","year":"2012","journal-title":"J. Immunol."},{"key":"2022071822160585500_CIT0015","doi-asserted-by":"crossref","first-page":"E1016","DOI":"10.1073\/pnas.1402391111","article-title":"Differential regulation of S-region hypermutation and class-switch recombination by noncanonical functions of uracil DNA glycosylase","volume":"111","author":"Yousif","year":"2014","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2022071822160585500_CIT0016","doi-asserted-by":"crossref","first-page":"2752","DOI":"10.1073\/pnas.0813252106","article-title":"Further evidence for involvement of a noncanonical function of uracil DNA glycosylase in class switch recombination","volume":"106","author":"Begum","year":"2009","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2022071822160585500_CIT0017","doi-asserted-by":"crossref","first-page":"22375","DOI":"10.1073\/pnas.0911879106","article-title":"AID-induced decrease in topoisomerase 1 induces DNA structural alteration and DNA cleavage for class switch recombination","volume":"106","author":"Kobayashi","year":"2009","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2022071822160585500_CIT0018","doi-asserted-by":"crossref","first-page":"19305","DOI":"10.1073\/pnas.1114522108","article-title":"Decrease in topoisomerase I is responsible for activation-induced cytidine deaminase (AID)-dependent somatic hypermutation","volume":"108","author":"Kobayashi","year":"2011","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2022071822160585500_CIT0019","doi-asserted-by":"crossref","first-page":"5791","DOI":"10.1073\/pnas.1506167112","article-title":"Identification of DNA cleavage- and recombination-specific hnRNP cofactors for activation-induced cytidine deaminase","volume":"112","author":"Hu","year":"2015","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2022071822160585500_CIT0020","doi-asserted-by":"crossref","first-page":"E1545","DOI":"10.1073\/pnas.1601678113","article-title":"Functional requirements of AID\u2019s higher order structures and their interaction with RNA-binding proteins","volume":"113","author":"Mondal","year":"2016","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2022071822160585500_CIT0021","doi-asserted-by":"crossref","first-page":"22190","DOI":"10.1073\/pnas.1016923108","article-title":"Histone3 lysine4 trimethylation regulated by the facilitates chromatin transcription complex is critical for DNA cleavage in class switch recombination","volume":"107","author":"Stanlie","year":"2010","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2022071822160585500_CIT0022","doi-asserted-by":"crossref","first-page":"10549","DOI":"10.1038\/ncomms10549","article-title":"Chromatin remodeller SMARCA4 recruits topoisomerase 1 and suppresses transcription-associated genomic instability","volume":"7","author":"Husain","year":"2016","journal-title":"Nat. Commun."},{"key":"2022071822160585500_CIT0023","doi-asserted-by":"crossref","first-page":"4193","DOI":"10.1073\/pnas.87.11.4193","article-title":"Yeast structural gene (APN1) for the major apurinic endonuclease: homology to Escherichia coli endonuclease IV","volume":"87","author":"Popoff","year":"1990","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2022071822160585500_CIT0024","doi-asserted-by":"crossref","first-page":"413","DOI":"10.5772\/53919","article-title":"DNA damage, dna repair and cancer","volume-title":"New Research Directions in DNA Repair","author":"Bernstein","year":"2013"},{"key":"2022071822160585500_CIT0025","volume-title":"Aging, Sex, and DNA Repair","author":"Bernstein","year":"1991"},{"key":"2022071822160585500_CIT0026","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1038\/362709a0","article-title":"Instability and decay of the primary structure of DNA","volume":"362","author":"Lindahl","year":"1993","journal-title":"Nature"},{"key":"2022071822160585500_CIT0027","doi-asserted-by":"crossref","first-page":"6750","DOI":"10.1038\/ncomms7750","article-title":"Mitochondrial function provides instructive signals for activation-induced B-cell fates","volume":"6","author":"Jang","year":"2015","journal-title":"Nat. Commun."},{"key":"2022071822160585500_CIT0028","doi-asserted-by":"crossref","first-page":"17242","DOI":"10.1073\/pnas.1420221111","article-title":"APE1 is dispensable for S-region cleavage but required for its repair in class switch recombination","volume":"111","author":"Xu","year":"2014","journal-title":"Proc. Natl Acad Sci. USA"},{"key":"2022071822160585500_CIT0029","doi-asserted-by":"crossref","first-page":"3703","DOI":"10.1021\/bi00129a020","article-title":"A novel, sensitive, and specific assay for abasic sites, the most commonly produced DNA lesion","volume":"31","author":"Kubo","year":"1992","journal-title":"Biochemistry"},{"key":"2022071822160585500_CIT0030","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/S0003-2670(97)00648-X","article-title":"Highly sensitive assay of DNA abasic sites in mammalian cells-optimization of the aldehyde reactive probe method","volume":"365","author":"Asaeda","year":"1998","journal-title":"Anal. Chim. Acta"},{"key":"2022071822160585500_CIT0031","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1038\/ni826","article-title":"AID-dependent somatic hypermutation occurs as a DNA single-strand event in the BL2 cell line","volume":"3","author":"Faili","year":"2002","journal-title":"Nat. Immunol."},{"key":"2022071822160585500_CIT0032","doi-asserted-by":"crossref","first-page":"2634","DOI":"10.1073\/pnas.0437710100","article-title":"De novo protein synthesis is required for the activation-induced cytidine deaminase function in class-switch recombination","volume":"100","author":"Doi","year":"2003","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2022071822160585500_CIT0033","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1128\/MCB.00026-13","article-title":"Apurinic\/apyrimidinic endonuclease 1 is the essential nuclease during immunoglobulin class switch recombination","volume":"33","author":"Masani","year":"2013","journal-title":"Mol. Cell. Biol."},{"key":"2022071822160585500_CIT0034","doi-asserted-by":"crossref","first-page":"1380","DOI":"10.1016\/j.cell.2013.08.021","article-title":"Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity","volume":"154","author":"Ran","year":"2013","journal-title":"Cell"},{"key":"2022071822160585500_CIT0035","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1016\/j.jmb.2011.06.050","article-title":"Characterization of the endoribonuclease active site of human apurinic\/apyrimidinic endonuclease 1","volume":"411","author":"Kim","year":"2011","journal-title":"J. Mol. Biol."},{"key":"2022071822160585500_CIT0036","doi-asserted-by":"crossref","first-page":"4029","DOI":"10.1182\/blood-2002-10-3175","article-title":"Chronic lymphocytic leukemia B cells expressing AID display dissociation between class switch recombination and somatic hypermutation","volume":"101","author":"Oppezzo","year":"2003","journal-title":"Blood"},{"key":"2022071822160585500_CIT0037","doi-asserted-by":"crossref","first-page":"7920","DOI":"10.1073\/pnas.1104423108","article-title":"Histone chaperone Spt6 is required for class switch recombination but not somatic hypermutation","volume":"108","author":"Okazaki","year":"2011","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2022071822160585500_CIT0038","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1073\/pnas.97.2.686","article-title":"A method for detecting abasic sites in living cells: age-dependent changes in base excision repair","volume":"97","author":"Atamna","year":"2000","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2022071822160585500_CIT0039","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/j.molcel.2004.12.029","article-title":"A vital role for Ape1\/Ref1 protein in repairing spontaneous DNA damage in human cells","volume":"17","author":"Fung","year":"2005","journal-title":"Mol. Cell"},{"key":"2022071822160585500_CIT0040","doi-asserted-by":"crossref","first-page":"3017","DOI":"10.1084\/jem.20071289","article-title":"APE1- and APE2-dependent DNA breaks in immunoglobulin class switch recombination","volume":"204","author":"Guikema","year":"2007","journal-title":"J. Exp. Med."},{"key":"2022071822160585500_CIT0041","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1038\/nature10102","article-title":"Genome-wide mapping of 5-hydroxymethylcytosine in embryonic stem cells","volume":"473","author":"Pastor","year":"2011","journal-title":"Nature"},{"key":"2022071822160585500_CIT0042","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1016\/S0022-2836(03)00712-5","article-title":"Properties of and substrate determinants for the exonuclease activity of human apurinic endonuclease Ape1","volume":"330","author":"Wilson","year":"2003","journal-title":"J. Mol. Biol."},{"key":"2022071822160585500_CIT0043","doi-asserted-by":"crossref","first-page":"2495","DOI":"10.1093\/nar\/25.12.2495","article-title":"3\u2019-phosphodiesterase activity of human apurinic\/apyrimidinic endonuclease at DNA double-strand break ends","volume":"25","author":"Suh","year":"1997","journal-title":"Nucleic Acids Res."}],"container-title":["International Immunology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/intimm\/advance-article-pdf\/doi\/10.1093\/intimm\/dxz028\/28486561\/dxz028.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/intimm\/article-pdf\/31\/8\/543\/45022630\/dxz028.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/intimm\/article-pdf\/31\/8\/543\/45022630\/dxz028.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,18]],"date-time":"2022-07-18T22:16:49Z","timestamp":1658182609000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/intimm\/article\/31\/8\/543\/5381903"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,3,16]]},"references-count":43,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2019,3,16]]},"published-print":{"date-parts":[[2019,7,30]]}},"URL":"https:\/\/doi.org\/10.1093\/intimm\/dxz028","relation":{},"ISSN":["1460-2377"],"issn-type":[{"value":"1460-2377","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,8]]},"published":{"date-parts":[[2019,3,16]]}}}