The JI
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     
 

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Bachl, J.
Right arrow Articles by Olsson, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bachl, J.
Right arrow Articles by Olsson, C.
The Journal of Immunology, 2001, 166: 5051-5057.
Copyright © 2001 by The American Association of Immunologists

Increased Transcription Levels Induce Higher Mutation Rates in a Hypermutating Cell Line1

Jürgen Bachl2,*,{dagger}, Chris Carlson*, Vanessa Gray-Schopfer*, Mark Dessing* and Carina Olsson*

* Basel Institute for Immunology, Basel, Switzerland; and {dagger} GSF-National Research Center for Environment and Health, Institute of Clinical Molecular Biology and Tumor Genetics, Munich, Germany

Somatic hypermutation, in addition to V(D)J recombination, is the other major mechanism that generates the vast diversity of the Ab repertoire. Point mutations are introduced in the variable region of the Ig genes at a million-fold higher rate than in the rest of the genome. We have used a green fluorescent protein (GFP)-based reversion assay to determine the role of transcription in the mutation mechanism of the hypermutating cell line 18-81. A GFP transgene containing a premature stop codon is transcribed from the inducible tet-on operon. Using the inducible promoter enables us to study the mutability of the GFP transgene at different transcription levels. By analyzing stable transfectants of a hypermutating cell line with flow cytometry, the mutation rate at the premature stop codon can be measured by the appearance of GFP-positive revertant cells. Here we show that the mutation rate of the GFP transgene correlates with its transcription level. Increased transcription levels of the GFP transgene caused an increased point mutation rate at the premature stop codon. Treating a hypermutating transfection clone with trichostatin A, a specific inhibitor of histone deacetylase, caused an additional 2-fold increase in the mutation rate. Finally, using Northern blot analysis we show that the activation-induced cytidine deaminase, an essential trans-factor for the in vivo hypermutation mechanism, is transcribed in the hypermutating cell line 18-81.




This article has been cited by other articles:


Home page
 JEMHome page
M. Seifert and R. Kuppers
Molecular footprints of a germinal center derivation of human IgM+(IgD+)CD27+ B cells and the dynamics of memory B cell generation
J. Exp. Med., November 23, 2009; 206(12): 2659 - 2669.
[Abstract] [Full Text] [PDF]

Home page
 FASEB J.Home page
C. Canugovi, M. Samaranayake, and A. S. Bhagwat
Transcriptional pausing and stalling causes multiple clustered mutations by human activation-induced deaminase
FASEB J, January 1, 2009; 23(1): 34 - 44.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
X. Wu, J. R. Darce, S. K. Chang, G. S. Nowakowski, and D. F. Jelinek
Alternative splicing regulates activation-induced cytidine deaminase (AID): implications for suppression of AID mutagenic activity in normal and malignant B cells
Blood, December 1, 2008; 112(12): 4675 - 4682.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
V. Shivarov, R. Shinkura, and T. Honjo
Dissociation of in vitro DNA deamination activity and physiological functions of AID mutants
PNAS, October 14, 2008; 105(41): 15866 - 15871.
[Abstract] [Full Text] [PDF]

Home page
 JEMHome page
S. Aoufouchi, A. Faili, C. Zober, O. D'Orlando, S. Weller, J.-C. Weill, and C.-A. Reynaud
Proteasomal degradation restricts the nuclear lifespan of AID
J. Exp. Med., June 9, 2008; 205(6): 1357 - 1368.
[Abstract] [Full Text] [PDF]

Home page
 GENES CELLSHome page
W. Lin, S.-i. Hashimoto, H. Seo, T. Shibata, and K. Ohta
Modulation of immunoglobulin gene conversion frequency and distribution by the histone deacetylase HDAC2 in chicken DT40.
Genes Cells, March 1, 2008; 13(3): 255 - 268.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
M. Larijani and A. Martin
Single-Stranded DNA Structure and Positional Context of the Target Cytidine Determine the Enzymatic Efficiency of AID
Mol. Cell. Biol., December 1, 2007; 27(23): 8038 - 8048.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
P. Perez-Duran, V. G. de Yebenes, and A. R. Ramiro
Oncogenic events triggered by AID, the adverse effect of antibody diversification
Carcinogenesis, December 1, 2007; 28(12): 2427 - 2433.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
S. Y. Yang, S. D. Fugmann, H. S. Gramlich, and D. G. Schatz
Activation-induced Cytidine Deaminase-mediated Sequence Diversification Is Transiently Targeted to Newly Integrated DNA Substrates
J. Biol. Chem., August 31, 2007; 282(35): 25308 - 25313.
[Abstract] [Full Text] [PDF]

Home page
 MicrobiologyHome page
E. Burkala, J. M. Reimers, K. H. Schmidt, N. Davis, P. Wei, and B. E. Wright
Secondary structures as predictors of mutation potential in the lacZ gene of Escherichia coli
Microbiology, July 1, 2007; 153(7): 2180 - 2189.
[Abstract] [Full Text] [PDF]

Home page
 JEMHome page
D. Ronai, M. D. Iglesias-Ussel, M. Fan, Z. Li, A. Martin, and M. D. Scharff
Detection of chromatin-associated single-stranded DNA in regions targeted for somatic hypermutation
J. Exp. Med., January 22, 2007; 204(1): 181 - 190.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
M. Larijani, A. P. Petrov, O. Kolenchenko, M. Berru, S. N. Krylov, and A. Martin
AID Associates with Single-Stranded DNA with High Affinity and a Long Complex Half-Life in a Sequence-Independent Manner
Mol. Cell. Biol., January 1, 2007; 27(1): 20 - 30.
[Abstract] [Full Text] [PDF]

Home page
 JEMHome page
S. Y. Yang, S. D. Fugmann, and D. G. Schatz
Control of gene conversion and somatic hypermutation by immunoglobulin promoter and enhancer sequences
J. Exp. Med., December 25, 2006; 203(13): 2919 - 2928.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
M. A. Inlay, H. H. Gao, V. H. Odegard, T. Lin, D. G. Schatz, and Y. Xu
Roles of the Ig {kappa} Light Chain Intronic and 3' Enhancers in Igk Somatic Hypermutation
J. Immunol., July 15, 2006; 177(2): 1146 - 1151.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
T. Muto, I.-m. Okazaki, S. Yamada, Y. Tanaka, K. Kinoshita, M. Muramatsu, H. Nagaoka, and T. Honjo
Negative regulation of activation-induced cytidine deaminase in B cells
PNAS, February 21, 2006; 103(8): 2752 - 2757.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
N. Kanayama, K. Todo, S. Takahashi, M. Magari, and H. Ohmori
Genetic manipulation of an exogenous non-immunoglobulin protein by gene conversion machinery in a chicken B cell line
Nucleic Acids Res., January 18, 2006; 34(2): e10 - e10.
[Abstract] [Full Text] [PDF]

Home page
 Int ImmunolHome page
K. Wakae, B. G. Magor, H. Saunders, H. Nagaoka, A. Kawamura, K. Kinoshita, T. Honjo, and M. Muramatsu
Evolution of class switch recombination function in fish activation-induced cytidine deaminase, AID
Int. Immunol., January 1, 2006; 18(1): 41 - 47.
[Abstract] [Full Text] [PDF]

Home page
 JEMHome page
S. Longerich, A. Tanaka, G. Bozek, D. Nicolae, and U. Storb
The very 5' end and the constant region of Ig genes are spared from somatic mutation because AID does not access these regions
J. Exp. Med., November 21, 2005; 202(10): 1443 - 1454.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
D. J. Araten, D. W. Golde, R. H. Zhang, H. T. Thaler, L. Gargiulo, R. Notaro, and L. Luzzatto
A Quantitative Measurement of the Human Somatic Mutation Rate
Cancer Res., September 15, 2005; 65(18): 8111 - 8117.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
D. Ronai, M. D. Iglesias-Ussel, M. Fan, M. J. Shulman, and M. D. Scharff
Complex regulation of somatic hypermutation by cis-acting sequences in the endogenous IgH gene in hybridoma cells
PNAS, August 16, 2005; 102(33): 11829 - 11834.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
C. L. Wang and M. Wabl
Hypermutation Rate Normalized by Chronological Time
J. Immunol., May 1, 2005; 174(9): 5650 - 5654.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
H. Nagaoka, S. Ito, M. Muramatsu, M. Nakata, and T. Honjo
DNA cleavage in immunoglobulin somatic hypermutation depends on de novo protein synthesis but not on uracil DNA glycosylase
PNAS, February 8, 2005; 102(6): 2022 - 2027.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
X. Wu, P. Geraldes, J. L. Platt, and M. Cascalho
The Double-Edged Sword of Activation-Induced Cytidine Deaminase
J. Immunol., January 15, 2005; 174(2): 934 - 941.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
L. Wang, W. C. Jackson, P. A. Steinbach, and R. Y. Tsien
Evolution of new nonantibody proteins via iterative somatic hypermutation
PNAS, November 30, 2004; 101(48): 16745 - 16749.
[Abstract] [Full Text] [PDF]

Home page
 Protein Eng Des SelHome page
C. L. Wang, D. C. Yang, and M. Wabl
Directed molecular evolution by somatic hypermutation
Protein Eng. Des. Sel., September 1, 2004; 17(9): 659 - 664.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
L. Delpy, C. Sirac, C. Le Morvan, and M. Cogne
Transcription-Dependent Somatic Hypermutation Occurs at Similar Levels on Functional and Nonfunctional Rearranged IgH Alleles
J. Immunol., August 1, 2004; 173(3): 1842 - 1848.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
F. J. X. Spillmann and M. Wabl
Endogenous Expression of Activation-Induced Cytidine Deaminase in Cell Line WEHI-231
J. Immunol., August 1, 2004; 173(3): 1858 - 1867.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
M. Cascalho
Advantages and Disadvantages of Cytidine Deamination
J. Immunol., June 1, 2004; 172(11): 6513 - 6518.
[Abstract] [Full Text] [PDF]

Home page
 JEMHome page
K. M. McBride, V. Barreto, A. R. Ramiro, P. Stavropoulos, and M. C. Nussenzweig
Somatic Hypermutation Is Limited by CRM1-dependent Nuclear Export of Activation-induced Deaminase
J. Exp. Med., May 3, 2004; 199(9): 1235 - 1244.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
K. Machida, K. T.-N. Cheng, V. M.-H. Sung, S. Shimodaira, K. L. Lindsay, A. M. Levine, M.-Y. Lai, and M. M. C. Lai
Hepatitis C virus induces a mutator phenotype: Enhanced mutations of immunoglobulin and protooncogenes
PNAS, March 23, 2004; 101(12): 4262 - 4267.
[Abstract] [Full Text] [PDF]

Home page
 Genes Dev.Home page
Z. Li, C. J. Woo, M. D. Iglesias-Ussel, D. Ronai, and M. D. Scharff
The generation of antibody diversity through somatic hypermutation and class switch recombination
Genes & Dev., January 1, 2004; 18(1): 1 - 11.
[Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
T. Eto, K. Kinoshita, K. Yoshikawa, M. Muramatsu, and T. Honjo
RNA-editing cytidine deaminase Apobec-1 is unable to induce somatic hypermutation in mammalian cells
PNAS, October 28, 2003; 100(22): 12895 - 12898.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
C. L. Morvan, E. Pinaud, C. Decourt, A. Cuvillier, and M. Cogne
The immunoglobulin heavy-chain locus hs3b and hs4 3' enhancers are dispensable for VDJ assembly and somatic hypermutation
Blood, August 15, 2003; 102(4): 1421 - 1427.
[Abstract] [Full Text] [PDF]

Home page
 JEMHome page
B. Reina-San-Martin, S. Difilippantonio, L. Hanitsch, R. F. Masilamani, A. Nussenzweig, and M. C. Nussenzweig
H2AX Is Required for Recombination Between Immunoglobulin Switch Regions but Not for Intra-Switch Region Recombination or Somatic Hypermutation
J. Exp. Med., June 16, 2003; 197(12): 1767 - 1778.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
A. Sohail, J. Klapacz, M. Samaranayake, A. Ullah, and A. S. Bhagwat
Human activation-induced cytidine deaminase causes transcription-dependent, strand-biased C to U deaminations
Nucleic Acids Res., June 15, 2003; 31(12): 2990 - 2994.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
M. S. Gordon, C. M. Kanegai, J. R. Doerr, and R. Wall
Somatic hypermutation of the B cell receptor genes B29 (Igbeta , CD79b) and mb1 (Igalpha , CD79a)
PNAS, April 1, 2003; 100(7): 4126 - 4131.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
A. Martin and M. D. Scharff
Somatic hypermutation of the AID transgene in B and non-B cells
PNAS, September 17, 2002; 99(19): 12304 - 12308.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
D. D. Dudley, J. P. Manis, A. A. Zarrin, L. Kaylor, M. Tian, and F. W. Alt
Internal IgH class switch region deletions are position-independent and enhanced by AID expression
PNAS, July 23, 2002; 99(15): 9984 - 9989.
[Abstract] [Full Text] [PDF]

Home page
 ScienceHome page
K. Yoshikawa, I.-m. Okazaki, T. Eto, K. Kinoshita, M. Muramatsu, H. Nagaoka, and T. Honjo
AID Enzyme-Induced Hypermutation in an Actively Transcribed Gene in Fibroblasts
Science, June 14, 2002; 296(5575): 2033 - 2036.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
X. Chen, K. Kinoshita, and T. Honjo
Variable deletion and duplication at recombination junction ends: Implication for staggered double-strand cleavage in class-switch recombination
PNAS, November 20, 2001; 98(24): 13860 - 13865.
[Abstract] [Full Text] [PDF]

Home page
 JEMHome page
C.-G. Lee, K. Kinoshita, A. Arudchandran, S. M. Cerritelli, R. J. Crouch, and T. Honjo
Quantitative Regulation of Class Switch Recombination by Switch Region Transcription
J. Exp. Med., August 6, 2001; 194(3): 365 - 374.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Website Copyright © 2001 by The American Association of Immunologists, Inc. All rights reserved.
All Contents Copyright © 2001 by The American Association of Immunologists, Inc. All rights reserved.