1. Cell Biology
  2. Structural Biology and Molecular Biophysics

The Nse5/6-like SIMC1-SLF2 complex localizes SMC5/6 to viral replication centers

  1. Martina Oravcová
  2. Minghua Nie
  3. Nicola Zilio
  4. Shintaro Maeda
  5. Yasaman Jami-Alahmadi
  6. Eros Lazzerini-Denchi
  7. James A Wohlschlegel
  8. Helle D Ulrich
  9. Takanori Otomo
  10. Michael Boddy  Is a corresponding author
  1. Scripps Research Institute, United States
  2. Institute of Molecular Biology, Germany
  3. University of California, Los Angeles, United States
  4. National Cancer Institute, United States
https://doi.org/10.7554/eLife.79676
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Cite this article
  1. Martina Oravcová
  2. Minghua Nie
  3. Nicola Zilio
  4. Shintaro Maeda
  5. Yasaman Jami-Alahmadi
  6. Eros Lazzerini-Denchi
  7. James A Wohlschlegel
  8. Helle D Ulrich
  9. Takanori Otomo
  10. Michael Boddy
(2022)
The Nse5/6-like SIMC1-SLF2 complex localizes SMC5/6 to viral replication centers
eLife 11:e79676.
https://doi.org/10.7554/eLife.79676
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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. SIMC1's 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 SIMC1's helical domain that regulates SMC5/6 localization to PyVRCs. Furthermore, SLF1, which recruits SMC5/6 to DNA lesions via its BRCT and ARD motifs, binds SLF2 analogously to SIMC1 and forms a separate Nse5/6-like complex. Thus, two Nse5/6-like complexes with distinct recruitment domains control human SMC5/6 localization.

Data availability

The SMC5 and SIMC1 BioID datasets have been deposited to the PRIDE database (85) as follows: Protein interaction AP-MS data: PRIDE PXD033923. Cryo-EM density map and atomic coordinates of the SIMC1-SLF2 complex have been deposited to the Electron Microscopy Data Bank and wwPDB, respectively, under accession codes EMD-25706 and PDB 7T5P.

The following data sets were generated

Article and author information

Author details

  1. Martina Oravcová

    Department of Molecular Medicine, Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Minghua Nie

    Department of Molecular Medicine, Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Nicola Zilio

    Institute of Molecular Biology, Mainz, Germany
    Competing interests
    The authors declare that no competing interests exist.

  4. Shintaro Maeda

    Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Yasaman Jami-Alahmadi

    Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Eros Lazzerini-Denchi

    Laboratory of Genome Integrity, National Cancer Institute, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. James A Wohlschlegel

    Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. Helle D Ulrich

    Institute of Molecular Biology, Mainz, Germany
    Competing interests
    The authors declare that no competing interests exist.

  9. Takanori Otomo

    Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3589-238X

  10. Michael Boddy

    Department of Molecular Medicine, Scripps Research Institute, La Jolla, United States
    For correspondence
    nboddy@scripps.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7618-4449

Funding

National Institute of General Medical Sciences (GM136273)

  • Michael Boddy

National Institute of General Medical Sciences (GM089788)

  • James A Wohlschlegel

National Institute of General Medical Sciences (GM092740)

  • Takanori Otomo

Deutsche Forschungsgemeinschaft (393547839 - SFB 1361,sub-project 07)

  • Helle D Ulrich

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Irene E Chiolo, University of Southern California, United States

Version history

  1. Received: April 22, 2022
  2. Preprint posted: May 19, 2022 (view preprint)
  3. Accepted: November 9, 2022
  4. Accepted Manuscript published: November 14, 2022 (version 1)
  5. Version of Record published: November 29, 2022 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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  1. Martina Oravcová
  2. Minghua Nie
  3. Nicola Zilio
  4. Shintaro Maeda
  5. Yasaman Jami-Alahmadi
  6. Eros Lazzerini-Denchi
  7. James A Wohlschlegel
  8. Helle D Ulrich
  9. Takanori Otomo
  10. Michael Boddy
(2022)
The Nse5/6-like SIMC1-SLF2 complex localizes SMC5/6 to viral replication centers
eLife 11:e79676.
https://doi.org/10.7554/eLife.79676

Share this article

https://doi.org/10.7554/eLife.79676

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