Principal Investigator: David B. Roth, MD, PhD
DNA Repair, Cancer Genetics, and Cancer Genomics
Understanding DNA double-strand break repair and genome rearrangements through V(D)J recombination
The Roth Lab studies the interface between V(D)J recombination and DNA repair, with a particular interest in the functions of the RAG proteins, the mechanisms of programmed gene rearrangements during lymphocyte differentiation, and the contribution of these rearrangements to lymphoid neoplasms.
Leukemias and lymphomas are common malignancies in humans, and a number of factors have been implicated in the etiology of these disorders. A large proportion of lymphoid neoplasms are born of chromosomal translocations involving antigen receptor loci. Up to 90% of cases of non-Hodgkin’s lymphoma, for instance, bear such translocations. V(D)J recombination, the process by which antigen receptor genes are rearranged in developing B and T cells, entails the cleavage and joining of gene segments millions of times each day. Although there are different stages of this process during which errors can occur, we are particularly interested in how the broken DNA is handed off by the V(D)J recombinase (the RAG proteins) to the proper DNA repair factors.
In the past few years our lab has shown that, in the context of V(D)J recombination, the RAG proteins serve as genome guardians by shepherding DNA breaks to one particular set of repair proteins: the nonhomologous end joining machinery (Lee, Cell, 2004; Corneo, Nature, 2007). Specific mutations in RAG1 or RAG2 can disrupt this guardian function, allowing RAG-generated breaks to be repaired instead by homologous recombination (Lee, Cell, 2004; Deriano, Nature 2011) or an alternative, poorly understood pathway known as alternative NHEJ. These mutations enhance lymphomagenesis in mouse models lacking p53 (Deriano, Nature, 2011; Gigi, Nucleic Acids Res, 2014).
We have recently analyzed these lymphomas using whole genome sequence analysis for rearrangements (Mijuskovic, PLOS 1, 2013), and found that while alternative NHEJ may play some role in oncogenic rearrangements (Gigi, Nucleic Acids Res 2014), recombination between DNA sequences that resemble RAG recognition sites appears to be the major mechanism driving lymphomagenesis. Analysis of multiple lymphomas from these models has allowed us to identify mutations in known, suspected, and previously unsuspected driver genes.