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Science 20 August 2004:
Vol. 305. no. 5687, pp. 1160 - 1163
DOI: 10.1126/science.1098444
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Reports

Uracil DNA Glycosylase Activity Is Dispensable for Immunoglobulin Class Switch

Nasim A. Begum,1 Kazuo Kinoshita,1 Naoki Kakazu,2 Masamichi Muramatsu,1 Hitoshi Nagaoka,1 Reiko Shinkura,1 Detlev Biniszkiewicz,3 Laurie A. Boyer,3 Rudolf Jaenisch,3 Tasuku Honjo1*

Activation-induced cytidine deaminase (AID) is required for the DNA cleavage step in immunoglobulin class switch recombination (CSR). AID is proposed to deaminate cytosine to generate uracil (U) in either mRNA or DNA. In the second instance, DNA cleavage depends on uracil DNA glycosylase (UNG) for removal of U. Using phosphorylated histone {gamma}-H2AX focus formation as a marker of DNA cleavage, we found that the UNG inhibitor Ugi did not inhibit DNA cleavage in immunoglobulin heavy chain (IgH) locus during CSR, even though Ugi blocked UNG binding to DNA and strongly inhibited CSR. Strikingly, UNG mutants that had lost the capability of removing U rescued CSR in UNG–/– B cells. These results indicate that UNG is involved in the repair step of CSRyet by an unknown mechanism. The dispensability of U removal in the DNA cleavage step of CSR requires a reconsideration of the model of DNA deamination by AID.

1 Department of Medical Chemistry and Molecular Biology, Graduate School of Medicine, Kyoto University, Yoshida Sakyo-ku, Kyoto 606-8501, Japan.
2 Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan.
3 Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.

* To whom correspondence should be addressed. E-mail: honjo{at}mfour.med.kyoto-u.ac.jp

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