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Antibody Class Switching Mediated by Yeast Endonuclease-Generated DNA Breaks
Ali A. Zarrin,1Catherine Del Vecchio,1Eva Tseng,1Megan Gleason,1Payam Zarin,1Ming Tian,2Frederick W. Alt1*
Antibody class switching in activated B cells uses class switchrecombination (CSR), which joins activation-induced cytidinedeaminase (AID)–dependent double-strand breaks (DSBs)within two large immunoglobulin heavy chain (IgH) locus switch(S) regions that lie up to 200 kilobases apart. To test postulatedroles of S regions and AID in CSR, we generated mutant B cellsin which donor Sµ and accepter S1 regions were replacedwith yeast I-SceI endonuclease sites. We found that site-specificI-SceI DSBs mediate recombinational IgH locus class switchingfrom IgM to IgG1 without S regions or AID. We propose that CSRevolved to exploit a general DNA repair process that promotesjoining of widely separated DSBs within a chromosome.
1 Howard Hughes Medical Institute, Children's Hospital, CBR Institute for Biomedical Research, and Department of Genetics, Harvard University Medical School, Boston, MA 02115, USA. 2 Department of Molecular Genetics and Microbiology, University of Texas at Austin, Austin, TX 78712, USA.
* To whom correspondence should be addressed. E-mail: alt{at}enders.tch.harvard.edu
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1 regions were replaced with yeast I-SceI endonuclease sites. We found that site-specific I-SceI DSBs mediate recombinational IgH locus class switching from IgM to IgG1 without S regions or AID. We propose that CSR evolved to exploit a general DNA repair process that promotes joining of widely separated DSBs within a chromosome. 
