As a first step towards addressing these questions, we performed a structure-function analysis of Smc5/6 to identify enzymatic activities and structural properties involved in its restriction function. Specifically, we tested individual Smc5/6 subunit mutants and/or naturally occurring isoforms with respect to their ability to promote episomal silencing using a functional complementation assay. We also explored whether the other members of the SMC family, cohesin and condensin, exhibited similar restriction activities. Our results reveal that episomal restriction is unique to Smc5/6. They further show that silencing is a three-step process that includes Smc5/6 binding to DNA, recruitment to promyelocytic leukemia nuclear bodies (PML-NBs) by SLF2 and silencing by a mechanism that involves a new function of Nse2. They also provide new information about how and under which circumstances the HBx protein interacts with Smc5/6, which may have therapeutic implications.