Published online 24 August 2004
Nucleic Acids Research, Vol. 32 No. 15 © Oxford University Press 2004; all rights reserved
Increased frequency of aberrant V(D)J recombination products in core RAG-expressing mice
Institute for Genome Research, University of Tokushima, Tokushima 770-8503, Japan and 1 Howard Hughes Medical Institute, Children's Hospital, Harvard Medical School, CBR Institute for Biomedical Research, Boston, MA 02115, USA
* To whom correspondence should be addressed. Tel: +1 510 574 1609; Fax: +1 510 574 1500; Email: yakamatsu{at}pdl.com
Present address: Yoshiko Akamatsu, Protein Design labs, Inc., 34801 Campus Drive, Fremont, CA 94555, USA
Received May 13, 2004; Revised and Accepted July 30, 2004
RAG1 and RAG2 play a central role in V(D)J recombination, a process for antigen receptor gene assembly. The truncated ‘core’ regions of RAGs are sufficient to catalyze the recombination reaction, although with lower joining efficiency than full-length proteins. To investigate the role of the non-core regions of RAGs in the end-joining phase of antigen receptor rearrangement, we analyzed recombination products isolated from core RAG1 and core RAG2 knock-in mice. Here, we report that the truncation of RAGs increases the frequency of aberrant recombination in vivo. Signal joints (SJs) associated with V-to-D recombination of core RAG1 knock-in mice were normal, whereas those of core RAG2 knock-in mice were highly imprecise, containing large deletions and additions, and in some cases coding sequences. In contrast, we found an elevated level of imprecise D-to-J associated SJs for both core RAG1- and RAG2-expressing mice. Likewise, sequences of coding joints (CJs) were also affected by the expression of core RAGs. Finally, sequences found at the junctions of rearranged T-cell receptor loci were highly influenced by differences in rearranging recombination signal sequence pairs. We provide the first evidence that the non-core regions of RAGs have critical functions in the proper assembly and resolution of recombination intermediates in endogenous antigen receptor loci.
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