SUMOylation is known to play important roles in the DNA damage response, however, a role for SUMOylation in interstrand crosslink repair remains enigmatic. We report on the regulation of the SLX4 nuclease scaffold protein by SUMOylation. SLX4 contains three SUMO-Interaction Motifs (SIMs). Mutating all three SIMs abrogated the binding of SLX4 to SUMO-2 and covalent SLX4 SUMOylation. We attempt to identify which protein interaction are SIM dependent.