A functional immune system is critical for the survival and health of humans and other vertebrate species. Central to the role of the immune system are the antigen receptor molecules, antibodies and T cell receptors, that mediate the specific recognition of an enormous number of foreign pathogens. The diversity required in these antigen receptors is generated by a series of specific rearrangement events, termed V(D)J recombination, in which the genomic DNA in lymphoid cells is cut and then rejoined in new combinations. Assembly of antigen receptors during lymphoid development presents an extremely complex regulatory problem, as well as a unique and intricate enzymatic pathway. Appropriate regulation is critical to prevent chromosomal breaks that could lead to translocations, or inappropriate antigen receptor assembly that could result in immune deficiency or autoimmunity. In addition, the repair and rejoining steps of the reaction rely on the same factors that repair other forms of DNA damage including x-ray induced double-strand breaks.

Projects in the Oettinger laboratory are focused on three areas of inquiry related to V(D)J recombination. First, we would like to understand how the assembly process is regulated. To this end, we are studying the role of chromatin and chromatin modifying activities on the accessibility of Ig and TCR loci to the recombinase machinery. Second, we are determining the detailed mechanistic action of the two proteins, RAG1 and RAG2, that collaborate to specifically cleave the DNA. Third, we are studying the factors involved in the repair of DNA double-strand breaks and working to identify additional proteins that are involved in the process. In doing so, we hope to define the molecular basis for some immunodeficiency syndromes and understand potential factors that lead to a predisposition to lymphoid malignancies.