Uracil DNA glycosylase activity is dispensable for immunloglobulin class switch

被引：94

作者：

Begum, NA

Kinoshita, K

Kakazu, N

Muramatsu, M

Nagaoka, H

Shinkura, R

Biniszkiewicz, D

Boyer, LA

Jaenisch, R

Honjo, T ^{[1
]}

机构：

[1] Kyoto Univ, Grad Sch Med, Dept Med Chem & Mol Biol, Sakyo Ku, Kyoto 6068501, Japan

[2] Kyoto Prefectural Univ Med, Grad Sch Med Sci, Dept Mol Targeting Canc Prevent, Kamigyo Ku, Kyoto 6028566, Japan

[3] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA

来源：

SCIENCE | 2004年 / 305卷 / 5687期

关键词：

D O I：

10.1126/science.1098444

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 CSR yet 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.

引用

收藏

页码：1160 / 1163

页数：4

相关论文

共 29 条

[1] Molecular mechanisms of apolipoprotein B mRNA editing [J].

Anant, S ;

Davidson, NO .

CURRENT OPINION IN LIPIDOLOGY, 2001, 12 (02) :159-165

[2] DNA-dependent protein kinase activity is not required for immunoglobulin class switching [J].

Bosma, GC ;

Kim, J ;

Urich, T ;

Fath, DM ;

Cotticelli, MG ;

Ruetsch, NR ;

Radic, MZ ;

Bosma, MJ .

JOURNAL OF EXPERIMENTAL MEDICINE, 2002, 196 (11) :1483-1495

[3] Genomic instability in mice lacking histone H2AX [J].

Celeste, A ;

Petersen, S ;

Romanienko, PJ ;

Fernandez-Capetillo, O ;

Chen, HT ;

Sedelnikova, OA ;

Reina-San-Martin, B ;

Coppola, V ;

Meffre, E ;

Difilippantonio, MJ ;

Redon, C ;

Pilch, DR ;

Olaru, A ;

Eckhaus, M ;

Camerini-Otero, RD ;

Tessarollo, L ;

Livak, F ;

Manova, K ;

Bonner, WM ;

Nussenzweig, MC ;

Nussenzweig, A .

SCIENCE, 2002, 296 (5569) :922-927

[4] Transcription-targeted DNA deamination by the AID antibody diversification enzyme [J].

Chaudhuri, J ;

Tian, M ;

Khuong, C ;

Chua, K ;

Pinaud, E ;

Alt, FW .

NATURE, 2003, 422 (6933) :726-730

[5] Vaccinia virus uracil DNA glycosylase has an essential role in DNA synthesis that is independent of its glycosylase activity: Catalytic-site, mutations reduce virulence but not virus replication in cultured cells [J].

De Silva, FS ;

Moss, B .

JOURNAL OF VIROLOGY, 2003, 77 (01) :159-166

[6] AID mediates hypermutation by deaminating single stranded DNA [J].

Dickerson, SK ;

Market, E ;

Besmer, E ;

Papavasiliou, EN .

JOURNAL OF EXPERIMENTAL MEDICINE, 2003, 197 (10) :1291-1296

[7] De novo protein synthesis is required for the activation-induced cytidine deaminase function in class-switch recombination [J].

Doi, T ;

Kinoshita, K ;

Ikegawa, M ;

Muramatsu, M ;

Honjo, T .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (05) :2634-2638

[8] A role for Saccharomyces cerevisiae histone H2A in DNA repair [J].

Downs, JA ;

Lowndes, NF ;

Jackson, SP .

NATURE, 2000, 408 (6815) :1001-1004

[9] AID: How does it aid antibody diversity? [J].

Honjo, T ;

Muramatsu, M ;

Fagarasan, S .

IMMUNITY, 2004, 20 (06) :659-668

[10] Molecular mechanism of class switch recombination: Linkage with somatic hypermutation [J].

Honjo, T ;

Kinoshita, K ;

Muramatsu, M .

ANNUAL REVIEW OF IMMUNOLOGY, 2002, 20 :165-196