The Nse5/6-like SIMC1-SLF2 complex localizes SMC5/6 to viral replication centers
- Scripps Research Institute, United States
- Institute of Molecular Biology, Germany
- University of California, Los Angeles, United States
- National Cancer Institute, United States
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.
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Cryo-EM structure of human SIMC1-SLF2 complexProtein Data Bank, 7T5P.
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Cryo-EM structure of human SIMC1-SLF2 complexElectron Microscopy Data Bank, EMD-25706.
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The Human Nse5 Orthologue SIMC1 Localizes SMC5/6 to Polyomavirus Replication CentersProteomics Identifications Database.
Article and author information
Author details
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
- Irene E Chiolo, University of Southern California, United States
Version history
- Received: April 22, 2022
- Preprint posted: May 19, 2022 (view preprint)
- Accepted: November 9, 2022
- Accepted Manuscript published: November 14, 2022 (version 1)
- 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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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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