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.
-
Cryo-EM structure of human SIMC1-SLF2 complexProtein Data Bank, 7T5P.
-
Cryo-EM structure of human SIMC1-SLF2 complexElectron Microscopy Data Bank, EMD-25706.
-
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.
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.
Metrics
-
- 1,872
- views
-
- 265
- downloads
-
- 13
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
The Nse5/6-like SIMC1-SLF2 complex localizes SMC5/6 to viral replication centers
eLife 11:e79676.
https://doi.org/10.7554/eLife.79676
Further reading
-
- Cell Biology
The accumulation of SIRT4 in the nuclei of kidney cells drives kidney fibrosis, so blocking the movement of this protein could be a potential therapeutic strategy against fibrosis.
-
- Cell Biology
- Developmental Biology
Chondrocyte columns, which are a hallmark of growth plate architecture, play a central role in bone elongation. Columns are formed by clonal expansion following rotation of the division plane, resulting in a stack of cells oriented parallel to the growth direction. In this work, we analyzed hundreds of Confetti multicolor clones in growth plates of mouse embryos using a pipeline comprising 3D imaging and algorithms for morphometric analysis. Surprisingly, analysis of the elevation angles between neighboring pairs of cells revealed that most cells did not display the typical stacking pattern associated with column formation, implying incomplete rotation of the division plane. Morphological analysis revealed that although embryonic clones were elongated, they formed clusters oriented perpendicular to the growth direction. Analysis of growth plates of postnatal mice revealed both complex columns, composed of ordered and disordered cell stacks, and small, disorganized clusters located in the outer edges. Finally, correlation between the temporal dynamics of the ratios between clusters and columns and between bone elongation and expansion suggests that clusters may promote expansion, whereas columns support elongation. Overall, our findings support the idea that modulations of division plane rotation of proliferating chondrocytes determines the formation of either clusters or columns, a multifunctional design that regulates morphogenesis throughout pre- and postnatal bone growth. Broadly, this work provides a new understanding of the cellular mechanisms underlying growth plate activity and bone elongation during development.
