My laboratory's research interests focus on the identification and characterization of signaling pathways that are activated in tumor cells treated with ionizing radiation or anti-tumor drugs. Our goal is to identify pivotal pathways that modulate and mediate tumor survival.

DNA-damaging agents and ionizing radiation are the mainstays of cancer treatment. In response to DNA damage and replication stress, cells activate the checkpoint signaling pathways, which regulate cell cycle progression, DNA repair, apoptosis, and gene transcription. Disruption of the checkpoint signaling pathways leads to increased sensitivity to DNA-damaging agents and genomic instability. Thus, a better understanding of the checkpoint signaling pathways may lead to more effective tumor therapies. My lab studies Rad9, Rad1, Hus1, and Rad17, four evolutionarily conserved checkpoint signaling proteins that are essential for checkpoint activation. Our studies demonstrate that Rad9, Hus1, and Rad1 form a heterotrimeric complex, dubbed the 9-1-1 complex. Biochemical analyses and modeling experiments suggest that the 9-1-1 complex forms a PCNA-like toroidal clamp that is clamped onto DNA at sites of DNA damage and at sites of where replication is inhibited. The clamp loader for 9-1-1 is Rad17, which is required for association of the 9-1-1 complex with damaged DNA. Although the 9-1-1 complex associates with DNA and is required for checkpoint activation, it is unclear how 9-1-1 participates in the activation of downstream signaling pathways. Currently, we are identifying proteins that interact with 9-1-1 and determining the role of 9-1-1 phosphorylation. Additionally, we are identifying the role of Rad17 in the clamp-loading reaction. Collectively, these studies will help identify key components of the signal transduction pathways that link DNA damage to the cellular responses that promote genomic stability and cell survival.