V(D)J recombination is the rearrangement of gene segments to assemble intact immunoglobulin and T cell receptor coding regions. This process is absolutely required for development of the immune system in jawed vertebrates such as humans, although its dysregulation can lead to leukemia or lymphoma. Rearrangement is initiated by a recombinase comprising the RAG1 and RAG2 proteins which cleaves the DNA adjacent to the V, D, and J gene segments. I have found that the zinc binding RING finger domain of RAG1 is a ubiquitin ligase that promotes covalent attachment of the small ubiquitin protein to a highly conserved lysine residue upstream of the RING finger and to other substrates in trans. Ubiquitylation is dependent on an intact RAG1 RING finger motif and is best promoted by a specific ubiquitin conjugating enzyme, UbcH3/CDC34. The significance of this activity is underscored by the finding that full length RAG1 is ubiquitylated in intact cells during G1, the phase of the cell cycle during which V(D)J recombination occurs. Although the RING finger lies outside of the RAG1 "core" domain which is absolutely required for DNA cleavage, mutations within the RING or truncation of the amino terminal regions are associated with severe immune deficiency in human patients. It is my hypothesis that RAG1’s ubiquitin ligase activity contributes to its biological role in B and T cell development by helping to regulate V(D)J recombination.

Selected Publications

C. Simkus, P. Anand, A. Bhattacharyya and J. M. Jones (2007) Biochemical and folding defects in a RAG1 variant associated with Omenn syndrome, J. Immunology, 179:8332-8340.

J. M. Jones and M. Gellert (2004)⌈ The taming of a transposon: V(D)J recombination and the immune system⌈, Immunological Reviews, 200:233-248

J. M. Jones and M. Gellert (2003)⌈ Auto-ubiquitylation of the V(D)J recombinase protein RAG1, ⌈PNAS, 100:15446-15451

J. M. Jones and M. Gellert (2002)⌈ Ordered assembly of the V(D)J synaptic complex ensures accurate recombination, ⌈EMBO J., 21: 4162-4171

M. Melek, J. M. Jones, M. H. O’dea, G. Pais, T. R. Burke, Y. Pommier, N. Neamati, and M. Gellert (2002) ⌈Effect of HIV integrase inhibitors on the RAG1/2 recombinase⌈, PNAS, 99: 134-137

J. M. Jones and M. Gellert (2001)⌈ Intermediates in V(D)J recombination: A stable RAG1/2 complex sequesters cleaved DNA ends⌈, PNAS, 98: 12926-12931

J.M. Jones, M. Gellert and W. Yang (2001) ⌈A Ku bridge over Broken DNA, ⌈Structure, 9: 881-884