Monoubiquitination is a highly regulated process conserved in all eukaryotes that controls a broad range of cellular functions, from signal transduction, vesicle trafficking, to DNA repair. Like phosphorylation, monoubiquitination is a dynamic and reversible post-translational process whereby an enzyme cascade conjugates ubiquitin to a target protein, and a family of enzymes, the deubiquitinating enzymes (DUBs), are potent at removing this modification. Two important DNA damage response pathways are ?switched on? by protein monoubiquitination: the downstream Fanconi Anemia (FA) effector protein, FANCD2, in DNA cross-link repair and the replication processivity factor, PCNA, in translesion DNA synthesis (TLS). While the elucidation of upstream activators of diverse DNA damage response pathways remains to be the focus of the field, signal transduction events that ?switch off? DNA repair have been largely ignored. To begin addressing this issue, a major focus of my lab will be to study the action of DUBs in the context of DNA repair pathways. In humans, protein deubiquitination is controlled by a family of over 90 distinct DUB enzymes, of which the majority has not been functionally characterized. In collaboration with the Rene Bernards? group, we utilized a gene family-specific siRNA library to identify DUBs that negatively regulated both FANCD2 and PCNA monoubiquitination. From this screen, the DUB, USP1, was discovered to have important roles in modulating two distinct DNA damage response pathways (see Fig. 1). Research projects in my lab will include the characterization and elucidation of signaling mechanisms surrounding DUB activation and inactivation and how these molecular events determine the status of genome stability and DNA damage tolerance pathways. Disruption of these pathways will ultimately lead to failed DNA repair, genome instability and cancer.