My broad research is the genetic regulation of DNA double strand break (DSB) repair and its impact on genome stability. One one hand, the generation of DNA DSBs is genetically programed and is involved in critical physiological processes such as the assembly and diversification of antigen receptors that ultimately lead to the production of antibodies and T cell receptors. On the other hand, DNA DSBs can be induced by exposure to genotoxic agents such as irradiation and chemotherapeutics.
Non-homologous end joining (NHEJ) and homologous recombination (HR) are the two major DSB repair pathways in cells. NHEJ is the only major DSB repair pathway available in G1 phase and is essential for V(D)J recombination, the assembly of antigen receptor genes. We have a long standing interest in elucidating the function of novel factors or genetic interactions in the repair of DNA DSBs generated during V(D)J recombination. These findings not only advance our understanding of V(D)J recombination and lymphocyte development, but also help uncover novel DSB repair genes that function in NHEJ.
The major determining factor of the choice or NHEJ and HR is the processing of DNA DSB ends by the process termed DNA end resection. We have begun addressing the spatial and temporal regulation DNA end processing so that cells can choose the proper and optimal DSB repair activities. To this end, we have recently conducted genome-wide CRISPR/Cas9 screens for genes that promote or inhibit DNA end resection. Our screens have uncovered novel genes in both categories. While our current focus is on the molecular function of these genes on DNA end processing, we have started to look into how manipulation of these genes can alter the activities of HR and NHEJ that will be beneficial for gene targeting and efficacy of cancer therapy involving chemotherapeutics and irradiation.
