The Journal of Experimental Medicine
Accuri Cytometers
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Published online 13 February 2006 doi:10.1084/jem.20052227
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 2, 319-323
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BRIEF DEFINITIVE REPORT

 Strand-biased defect in C/G transversions in hypermutating immunoglobulin genes in Rev1-deficient mice

Jacob G. Jansen1, Petra Langerak2, Anastasia Tsaalbi-Shtylik1, Paul van den Berk2, Heinz Jacobs2, and Niels de Wind1

1 Department of Toxicogenetics, Leiden University Medical Center, 2300 RC Leiden, Netherlands
2 Division of Immunology, The Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands

CORRESPONDENCE Niels de Wind: N.de_wind{at}lumc.nl

Somatic hypermutation of Ig genes enables B cells of the germinal center to generate high-affinity immunoglobulin variants. Key intermediates in somatic hypermutation are deoxyuridine lesions, introduced by activation-induced cytidine deaminase. These lesions can be processed further to abasic sites by uracil DNA glycosylase. Mutagenic replication of deoxyuridine, or of its abasic derivative, by translesion synthesis polymerases is hypothesized to underlie somatic hypermutation.

Rev1 is a translesion synthesis polymerase that in vitro incorporates uniquely deoxycytidine opposite deoxyuridine and abasic residues. To investigate a role of Rev1 in mammalian somatic hypermutation we have generated mice deficient for Rev1. Although Rev1–/– mice display transient growth retardation, proliferation of Rev1–/– LPS-stimulated B cells is indistinguishable from wild-type cells. In mutated Ig genes from Rev1–/– mice, C to G transversions were virtually absent in the nontranscribed (coding) strand and reduced in the transcribed strand. This defect is associated with an increase of A to T, C to A, and T to C substitutions. These results indicate that Rev1 incorporates deoxycytidine residues, most likely opposite abasic nucleotides, during somatic hypermutation. In addition, loss of Rev1 causes compensatory increase in mutagenesis by other translesion synthesis polymerases.

J.G. Jansen, P. Langerak, H. Jacobs, and N. de Wind contributed equally to this work.


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