Carcinogenesis Advance Access originally published online on January 30, 2004
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Carcinogenesis, Vol. 25, No. 6, 1069-1075,
June 2004
Carcinogenesis vol.25 no.6 © Oxford University Press 2004; all rights reserved.
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Involvement of V(D)J recombinase in the generation of intragenic deletions in the Rit1/Bcl11b tumor suppressor gene in 
-ray-induced thymic lymphomas and in normal thymus of the mouse
1 Department of Molecular Genetics and 2 Department of Regenerative and Transplant Medicine, Graduate School of Medical and Dental Sciences and 3 Center for Transdisciplinary Research, Niigata University, Asahimachi 1-757, Niigata 951-8122, Japan and 4 Radiation Biology Center, Kyoto University, Yoshida-Konoecho, Sakyou-Ku, Kyoto, 606-8315, Japan
5 To whom correspondence should be addressed at: Department of Molecular Genetics, Graduate School of Medical and Dental Sciences, Niigata University, Asahimachi 1-757, Niigata 951-8122, Japan Email: rykomina{at}med.niigata-u.ac.jp
Mouse thymic lymphomas induced by 
-irradiation exhibited homozygous deletions of the Rit1/Bcl11b tumor suppressor gene on chromosome 12 at high frequencies. Internal deletions of one allele were frequently accompanied by loss of the other allele. In order to elucidate the mechanism of these internal deletions, the sites of breakage and rejoining were examined by PCR mapping and sequencing. The 5' site of the deletions clustered within an 
5 kb region of intron 1 and the 3' site was confined to a site in intron 3. These sites contained P and/or N nucleotides and cryptic sequences recognizable by the RAG1/2 recombinase in the vicinity. This suggests that the Rit1 intragenic deletions were generated by endogenous illegitimate V(D)J recombinase activity and such aberrant recombination was also detected by nested PCR of DNA from the thymus of unirradiated mice but not of RAG2-deficient mice. A rough estimate indicated that there reside as many as 103–104 thymocytes having Rit1 deletions, assuming the presence of 108 thymocytes in the thymus of unirradiated mice. Moreover, the recombination frequency was not affected by -irradiation. These results show no effect of radiation on Rit1 mutations and suggest an indirect mechanism for its role in lymphomagenesis.
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