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Molecular and Cellular Biology, January 2001, p. 400-413, Vol. 21, No. 2
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.2.400-413.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Irradiation Promotes V(D)J Joining and RAG-Dependent Neoplastic Transformation in SCID T-Cell Precursors

Christine J. Williams,dagger Ildiko Grandal, Danny J. Vesprini, Urszula Wojtyra, Jayne S. Danska, and Cynthia J. Guidos*

Hospital for Sick Children Research Institute and Department of Immunology, University of Toronto, Toronto, Ontario, Canada

Received 31 July 2000/Returned for modification 8 September 2000/Accepted 17 October 2000

Defects in the nonhomologous end-joining (NHEJ) pathway of double-stranded DNA break repair severely impair V(D)J joining and selectively predispose mice to the development of lymphoid neoplasia. This connection was first noted in mice with the severe combined immune deficient (SCID) mutation in the DNA-dependent protein kinase (DNA-PK). SCID mice spontaneously develop thymic lymphoma with low incidence and long latency. However, we and others showed that low-dose irradiation of SCID mice dramatically increases the frequency and decreases the latency of thymic lymphomagenesis, but irradiation does not promote the development of other tumors. We have used this model to explore the mechanistic basis by which defects in NHEJ confer selective and profound susceptibility to lymphoid oncogenesis. Here, we show that radiation quantitatively and qualitatively improves V(D)J joining in SCID cells, in the absence of T-cell receptor-mediated cellular selection. Furthermore, we show that the lymphocyte-specific endonuclease encoded by the recombinase-activating genes (RAG-1 and RAG-2) is required for radiation-induced thymic lymphomagenesis in SCID mice. Collectively, these data suggest that irradiation induces a DNA-PK-independent NHEJ pathway that facilitates V(D)J joining, but also promotes oncogenic misjoining of RAG-1/2-induced breaks in SCID T-cell precursors.

* Corresponding author. Mailing address: Program in Developmental Biology, Rm. 8104, Hospital for Sick Children Research Institute, 555 University Ave., Toronto, Ontario M5G 1X8, Canada. Phone: (416) 813-8810. Fax: (416) 813-8823. E-mail: guidos{at}sickkids.on.ca.

dagger Present address: Cutaneous Biology Research Center, Massachusetts General Hospital East, Charlestown, MA 02129.

Molecular and Cellular Biology, January 2001, p. 400-413, Vol. 21, No. 2
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.2.400-413.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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