The Nse5/6-like SIMC1-SLF2 Complex Localizes SMC5/6 to Viral Replication Centers

Oravcova, M.; Nie, M.; Zilio, N.; Maeda, S.; Jami-Alahmadi, Y.; Lazzerini-Denchi, E.; Wohlschlegel, J. A.; Ulrich, H.; Otomo, T.; Boddy, M.

doi:10.1101/2022.05.17.492321

bioRxiv · 10.1101/2022.05.17.492321

The Nse5/6-like SIMC1-SLF2 Complex Localizes SMC5/6 to Viral Replication Centers

Oravcova, M.·Nie, M.·Zilio, N.·Maeda, S.·Jami-Alahmadi, Y.·Lazzerini-Denchi, E.·Wohlschlegel, J. A.·Ulrich, H.·Otomo, T.·Boddy, M.

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Abstract

The human SMC5/6 complex is a conserved guardian of genome stability and an emerging component of antiviral responses. These disparate functions likely require distinct mechanisms of SMC5/6 regulation. In yeast, Smc5/6 is regulated by its Nse5/6 subunits, but such regulatory subunits for human SMC5/6 are poorly defined. Here, we identify a novel SMC5/6 subunit called SIMC1 that contains SUMO interacting motifs (SIMs) and an Nse5-like domain. We isolated SIMC1 from the proteomic environment of SMC5/6 within polyomavirus large T antigen (LT)-induced subnuclear compartments. SIMC1 uses its SIMs and Nse5-like domain to localize SMC5/6 to polyomavirus replication centers (PyVRCs) at SUMO-rich PML nuclear bodies. SIMC1s Nse5-like domain binds to the putative Nse6 orthologue SLF2 to form an anti-parallel helical dimer resembling the yeast Nse5/6 structure. SIMC1-SLF2 structure-based mutagenesis defines a conserved surface region containing the N-terminus of SIMC1s helical domain that regulates SMC5/6 localization to PyVRCs. Furthermore, SLF1, which recruits SMC5/6 to DNA lesions, binds SLF2 analogously to SIMC1 and forms a distinct Nse5/6-like complex. Thus, two Nse5/6-like complexes independently regulate human SMC5/6: SIMC1-SLF2 responding to viral challenge and SLF1/2 recognizing DNA damage.

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Oravcova, M., Nie, M., Zilio, N., Maeda, S., Jami-Alahmadi, Y., Lazzerini-Denchi, E., Wohlschlegel, J. A., Ulrich, H., Otomo, T., Boddy, M.. 2022-05-19. The Nse5/6-like SIMC1-SLF2 Complex Localizes SMC5/6 to Viral Replication Centers. https://doi.org/10.1101/2022.05.17.492321

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