TOPORS is the first example of a protein with both ubiquitin and SUMO-1 E3 ligase activity and has been implicated as a tumor suppressor in several different malignancies. To gain insight into the cellular role of TOPORS, a proteomic screen was performed to identify candidate sumoylation substrates. The results indicate that many of the putative substrates are involved in chromatin modification or transcriptional regulation. Transfection studies confirmed mammalian Sin3A as a sumoylation substrate for TOPORS. These findings suggest that TOPORS may function as a tumor suppressor by regulating mSin3A and other proteins involved in chromatin modification.