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Originally published in Science Express on 14 December 2006
Science 19 January 2007:
Vol. 315. no. 5810, pp. 377 - 381
DOI: 10.1126/science.1136386
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Reports

Antibody Class Switching Mediated by Yeast Endonuclease-Generated DNA Breaks

Ali A. Zarrin,1 Catherine Del Vecchio,1 Eva Tseng,1 Megan Gleason,1 Payam Zarin,1 Ming Tian,2 Frederick W. Alt1*

Antibody class switching in activated B cells uses class switch recombination (CSR), which joins activation-induced cytidine deaminase (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 postulated roles of S regions and AID in CSR, we generated mutant B cells in which donor Sµ and accepter S{gamma}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.

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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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
S{gamma}3 switch sequences function in place of endogenous S{gamma}1 to mediate antibody class switching.
A. A. Zarrin, P. H. Goff, K. Senger, and F. W. Alt (2008)
J. Exp. Med. 205, 1567-1572
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From the Cover: Antisense transcripts from immunoglobulin heavy-chain locus V(D)J and switch regions.
T. Perlot, G. Li, and F. W. Alt (2008)
PNAS 105, 3843-3848
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Dependence of antibody gene diversification on uracil excision.
J. M. Di Noia, G. T. Williams, D. T.Y. Chan, J.-M. Buerstedde, G. S. Baldwin, and M. S. Neuberger (2007)
J. Exp. Med. 204, 3209-3219
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APE1- and APE2-dependent DNA breaks in immunoglobulin class switch recombination.
J. E.J. Guikema, E. K. Linehan, D. Tsuchimoto, Y. Nakabeppu, P. R. Strauss, J. Stavnezer, and C. E. Schrader (2007)
J. Exp. Med. 204, 3017-3026
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Immune Complex Pathophysiology.
U. E. NYDEGGER (2007)
Ann. N.Y. Acad. Sci. 1109, 66-83
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DNA polymerase {beta} is able to repair breaks in switch regions and plays an inhibitory role during immunoglobulin class switch recombination.
X. Wu and J. Stavnezer (2007)
J. Exp. Med. 204, 1677-1689
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