The Human Nse5 Orthologue SIMC1 Localizes SMC5/6 to Polyomavirus Replication Centers

The human SMC5-SMC6 complex (SMC5/6) is a conserved guardian of genome stability and an emerging component of the antiviral response in animals and plants. In yeast, Smc5/6 is recruited to and loaded on chromatin by the poorly conserved Nse5-Nse6 heterodimer (Nse5/6), which remains largely undefined in humans. Here we report that SIMC1 is an Nse5 orthologue and novel subunit of the human SMC5/6 complex. SIMC1 binds to SLF2, the proposed Nse6 orthologue, forming a stable complex structurally similar to yeast Nse5/6. SIMC1 localizes SMC5/6 to polyomavirus replication centers in a SUMO interaction-dependent manner. Further structure prediction analyses indicate that SLF1, a putative Nse5 counterpart that recruits SMC5/6 to DNA lesions, interacts with SLF2 in a very similar manner as SIMC1. Consistently, SIMC1 and SLF1 form mutually exclusive complexes with SLF2. Thus, both SIMC1 and SLF1 act as orthologues of yeast Nse5 to independently direct the functions of SMC5/6.