Irradiation promotes V(D)J joining and RAG-dependent neoplastic transformation in SCID T-cell precursors.
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.
Williams
C J
CJ
Hospital for Sick Children Research Institute and Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
Grandal
I
I
Vesprini
D J
DJ
Wojtyra
U
U
Danska
J S
JS
Guidos
C J
CJ
D000818:Animals; D001483:Base Sequence; D002455:Cell Division / Q000528:radiation effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000528:radiation effects*; D022801:Complementarity Determining Regions / Q000235:genetics*; D004249:DNA Damage; D004254:DNA Nucleotidyltransferases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D015329:Gene Rearrangement, T-Lymphocyte / Q000235:genetics / Q000528:radiation effects*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D008223:Lymphoma / Q000235:genetics / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000502:physiology; D011995:Recombination, Genetic / Q000235:genetics / Q000528:radiation effects*; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D013953:Thymus Neoplasms / Q000235:genetics / Q000473:pathology; D019076:Transgenes / Q000235:genetics; D014407:Tumor Cells, Cultured; D045567:VDJ Recombinases
D022801:Complementarity Determining Regions; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D012333:RNA, Messenger; C499308:Rag2 protein, mouse; D011948:Receptors, Antigen, T-Cell; C064655:V(D)J recombination activating protein 2; C064658:RAG-1 protein; D004254:DNA Nucleotidyltransferases; D045567:VDJ Recombinases