The objective of this proposal is to gain an understanding of the molecular mechanisms of lymphoid V(D)J recombination and DNA double-strand break (DSB) repair. These two pathways share at least one common factor, the SCID (severe combined immune deficiency) gene product and probably share many others. In particular, we intend to determine whether this overlap can be extended to the murine wasted mutation, which confers onto affected animals a severe immune deficiency and a sensitivity to ionizing radiation. The high cancer rate associated with DNA repair defects suggests that generalized DSB repair is also critical for many other important biological processes including chromosome integrity and stability, mutagenesis and carcinogenesis as well as lymphoid V(D)J recombination. These two important biological pathways will be characterized using 3 lines of experimentation: 1)Does the wasted (wst) mutation affect the process of V(D)J recombination? 2)What are the DNA repair defects associated with the wst and scid mutations? 3)Do the scid and wst mutations affect homologous and/or illegitimate (non-homologous) recombination? %%%% The ultimate goal of these studies will be to use the scid and wst mutations as tools to understand the molecular mechanisms of lymphoid gene rearrangement and DNA repair.
