{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T09:29:46Z","timestamp":1771493386505,"version":"3.50.1"},"reference-count":47,"publisher":"Proceedings of the National Academy of Sciences","issue":"7","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2010,2,16]]},"abstract":"<jats:p>\n            Class switch recombination (CSR) in B lymphocytes is initiated by introduction of multiple DNA double-strand breaks (DSBs) into switch (S) regions that flank immunoglobulin heavy chain (\n            <jats:italic>IgH<\/jats:italic>\n            ) constant region exons. CSR is completed by joining a DSB in the donor S\u03bc to a DSB in a downstream acceptor S region (e.g., S\u03b31) by end-joining. In normal cells, many CSR junctions are mediated by classical nonhomologous end-joining (C-NHEJ), which employs the Ku70\/80 complex for DSB recognition and XRCC4\/DNA ligase 4 for ligation. Alternative end-joining (A-EJ) mediates CSR, at reduced levels, in the absence of C-NHEJ, even in combined absence of Ku70 and ligase 4, demonstrating an A-EJ pathway totally distinct from C-NHEJ. Multiple DSBs are introduced into S\u03bc during CSR, with some being rejoined or joined to each other to generate internal switch deletions (ISDs). In addition, S-region DSBs can be joined to other chromosomes to generate translocations, the level of which is increased by absence of a single C-NHEJ component (e.g., XRCC4). We asked whether ISD and S-region translocations occur in the complete absence of C-NHEJ (e.g., in Ku70\/ligase 4 double-deficient B cells). We found, unexpectedly, that B-cell activation for CSR generates substantial ISD in both S\u03bc and S\u03b31 and that ISD in both is greatly increased by the absence of C-NHEJ.\n            <jats:italic>IgH<\/jats:italic>\n            chromosomal translocations to the\n            <jats:italic>c-myc<\/jats:italic>\n            oncogene also are augmented in the combined absence of Ku70 and ligase 4. We discuss the implications of these findings for A-EJ in normal and abnormal DSB repair.\n          <\/jats:p>","DOI":"10.1073\/pnas.0915067107","type":"journal-article","created":{"date-parts":[[2010,1,26]],"date-time":"2010-01-26T02:54:47Z","timestamp":1264474487000},"page":"3034-3039","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":164,"title":["Alternative end-joining catalyzes robust IgH locus deletions and translocations in the combined absence of ligase 4 and Ku70"],"prefix":"10.1073","volume":"107","author":[{"given":"Cristian","family":"Boboila","sequence":"first","affiliation":[{"name":"Department of Genetics, Harvard Medical School;"},{"name":"The Children\u2019s Hospital;"},{"name":"Immune Disease Institute;"},{"name":"Howard Hughes Medical Institute, Boston, MA 02115;"}]},{"given":"Mila","family":"Jankovic","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Immunology, The Rockefeller University, New York, NY, 10065;"}]},{"given":"Catherine T.","family":"Yan","sequence":"additional","affiliation":[{"name":"Division of Experimental Pathology, Pathology Department, Beth Israel Deaconess Medical Center, Boston, MA 02115;"}]},{"given":"Jing H.","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Genetics, Harvard Medical School;"},{"name":"The Children\u2019s Hospital;"},{"name":"Immune Disease Institute;"},{"name":"Howard Hughes Medical Institute, Boston, MA 02115;"}]},{"given":"Duane R.","family":"Wesemann","sequence":"additional","affiliation":[{"name":"Department of Genetics, Harvard Medical School;"},{"name":"The Children\u2019s Hospital;"},{"name":"Immune Disease Institute;"},{"name":"Howard Hughes Medical Institute, Boston, MA 02115;"},{"name":"Division of Rheumatology, Allergy and Immunology, Department of Medicine, Brigham and Women\u2019s Hospital, Boston, MA 02115;"}]},{"given":"Tingting","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Genetics, Harvard Medical School;"},{"name":"The Children\u2019s Hospital;"},{"name":"Immune Disease Institute;"},{"name":"Howard Hughes Medical Institute, Boston, MA 02115;"}]},{"given":"Alex","family":"Fazeli","sequence":"additional","affiliation":[{"name":"Department of Genetics, Harvard Medical School;"},{"name":"The Children\u2019s Hospital;"},{"name":"Immune Disease Institute;"},{"name":"Howard Hughes Medical Institute, Boston, MA 02115;"}]},{"given":"Lauren","family":"Feldman","sequence":"additional","affiliation":[{"name":"Division of Experimental Pathology, Pathology Department, Beth Israel Deaconess Medical Center, Boston, MA 02115;"}]},{"given":"Andre","family":"Nussenzweig","sequence":"additional","affiliation":[{"name":"Experimental Immunology Branch, National Cancer Institute; and"},{"name":"National Institutes of Health, Bethesda, MD 20892"}]},{"given":"Michel","family":"Nussenzweig","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute, Boston, MA 02115;"},{"name":"Laboratory of Molecular Immunology, The Rockefeller University, New York, NY, 10065;"}]},{"given":"Frederick W.","family":"Alt","sequence":"additional","affiliation":[{"name":"Department of Genetics, Harvard Medical School;"},{"name":"The Children\u2019s Hospital;"},{"name":"Immune Disease Institute;"},{"name":"Howard Hughes Medical Institute, Boston, MA 02115;"}]}],"member":"341","published-online":{"date-parts":[[2010,1,25]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.20.090501.112049"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-2776(06)94006-1"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)00078-7"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/414660a"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.171.5.2504"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/cdg550"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2004.05.011"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/296325a0"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(90)90248-D"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90644-6"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.152333499"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20030569"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20041162"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature06020"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2007.108"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.0105-2896.2004.00165.x"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20080044"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2009.04.025"},{"key":"e_1_3_3_19_2","article-title":"Alternative end-joining catalyzes class switch recombination in the absence of both Ku70 and DNA ligase 4","author":"Boboila C","year":"2009","unstructured":"C Boboila, et al., Alternative end-joining catalyzes class switch recombination in the absence of both Ku70 and DNA ligase 4. 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