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【免疫システム】免疫抗体遺伝子の改変 機構の一部を解明、京大教授ら(04/08/20)

2 :( メ`ω´)φ ★:04/08/20 13:42 ID:???
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【Uracil DNA Glycosylase Activity Is Dispensable for Immunoglobulin Class Switch 】
Science, Vol 305, Issue 5687, 1160-1163 , 20 August 2004
DOI: 10.1126/science.1098444

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 -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.


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