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Review
. 2023 Jun;30(6):724-734.
doi: 10.1038/s41594-023-01015-6. Epub 2023 Jun 19.

The multi-functional Smc5/6 complex in genome protection and disease

Xiao P Peng  1 , Xiaolan Zhao  2
Affiliations
Review

The multi-functional Smc5/6 complex in genome protection and disease

Xiao P Peng et al. Nat Struct Mol Biol. 2023 Jun.

Abstract

Structural maintenance of chromosomes (SMC) complexes are ubiquitous genome regulators with a wide range of functions. Among the three types of SMC complexes in eukaryotes, cohesin and condensin fold the genome into different domains and structures, while Smc5/6 plays direct roles in promoting chromosomal replication and repair and in restraining pathogenic viral extra-chromosomal DNA. The importance of Smc5/6 for growth, genotoxin resistance and host defense across species is highlighted by its involvement in disease prevention in plants and animals. Accelerated progress in recent years, including structural and single-molecule studies, has begun to provide greater insights into the mechanisms underlying Smc5/6 functions. Here we integrate a broad range of recent studies on Smc5/6 to identify emerging features of this unique SMC complex and to explain its diverse cellular functions and roles in disease pathogenesis. We also highlight many key areas requiring further investigation for achieving coherent views of Smc5/6-driven mechanisms.

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Conflict of interest statement

Competing interests

The authors declare no competing interests.

Figures

Fig. 1 |
Fig. 1 |. Architecture of the Smc5/6 complex.
a, Diagrams showing the SMC protein domains and folding mechanisms. See main text for details. b, Diagrams showing a model of the budding yeast Smc5/6 architecture and subunit activities. See main text for details. Subunit colors are used consistently in all panels: Smc5, light gray; Smc6, dark gray; Nse1, gold; Nse2, cyan; Nse3, orange; Nse4, pink; Nse5, dark purple; Nse6, dark blue. As detailed in the text, Nse2 and Nse1 exhibit SUMO and ubiquitin (Ub) E3 activities, respectively, while Nse4 is the kleisin subunit. c, A medium-resolution cryo-EM structure of the budding yeast Smc5/6 hexamer complex, which contains Smc5–6 and Nse1–4, but lacks Nse5–6. Panel c adapted under a Creative Commons license CC BY 4.0 from Hallett et al..
Fig. 2 |
Fig. 2 |. Structures of different subunits and subcomplexes of the Smc5/6 complex.
a, Crystal structure of the budding yeast SUMO E3 subunit Nse2 (cyan) bound to a region of the Smc5 arm (light gray) (PDB 3HTK). Spheres indicate zinc ions in the SUMO E3 domain. b, Cryo-EM structure of the budding yeast Nse5–6 subcomplex (PDB 7SDE), showing the Nse5 (dark purple) and Nse6 (dark blue) dimerization domains. c, Crystal structure of the Rtt107 tetra-BRCT domain (green, transparent) bound to the Rtt107 interaction motif (RIM, dark blue) of Nse6 (PDB 6J0W). d, Crystal structure of the Xenopus Nse1–3-4 complex, with Nse1 shown in gold, Nse3 orange and Nse4 pink (PDB 7DG2). Spheres indicate zinc ions incorporated in the Nse1 ubiquitin E3 domain. e, Cryo-EM structure of the budding yeast Smc5/6 hexamer bound to ATP and dsDNA (yellow) (PDB 7TVE). Colors of proteins are as in Fig. 1b,c. f, Crystal structure of the hinge regions of fission yeast Smc5–6 (PDB 5MG8). g, Crystal structure of the Nse2 SUMO E3 subunit (cyan) bound to the Smc5 arm (light gray) and SUMO E2 Ubc9 (light green). Ubc9 is conjugated with a donor SUMO (SUMOD, purple) and binds to a backside SUMO (SUMOB, purple) (PDB 7P47). Figures adapted with permission from: a, Duan et al., Elsevier; b, Yu et al., PNAS; c, Wan et al., Elsevier; d, Jo et al., Elsevier; e, Yu et al., PNAS; f, Alt et al., Springer Nature; g, Varejao et al., Springer Nature.
Fig. 3 |
Fig. 3 |. Multifaceted roles of Smc5/6 in recombinational repair and DNA replication.
a, The multiple roles played by Smc5/6 during recombinational repair. See main text for details. b, Smc5/6’s effects on DNA replication based on studies in budding yeast. Left: Smc5/6 has at least two roles in helping rDNA replication and stability: (i) negative regulation of Mph1-mediated replication fork reversal at replication fork pausing sites marked by the Fob1 protein and (ii) collaboration with the Cohibin and CLIP complexes. Right: Smc5/6 cooperates with the STR complex for proper replication termination. c, Examples of SUMO-based regulation of DNA replication by the yeast Smc5/6 complex. Smc5/6 promotes sumoylation of the ssDNA binding complex RPA, the leading-strand DNA polymerase subunit Pol2, and Smc5 itself. The consequence of each modification is indicated and explained in the text.
Fig. 4 |
Fig. 4 |. Summary of phenotypes caused by defective Smc5/6 in mammalian systems.
a, Cellular defects reported for SMC5/6 LOF in mammalian systems. SMC5/6 deficiencies lead to increased levels of replication stress markers and abnormal chromosome structures (arrows) (top), as well as impairments in growth, telomere maintenance, and survival of replication stress and radiation (bottom),,,,,,–. b, Clinical phenotypes of SMC5/6-deficient individuals overlap those of other genome instability syndromes caused by mutations in genes encoding BTR and FA proteins and leading-strand DNA polymerases (POLE1 and POLE2). Individual features are shown for germline mutations in NSMCE2, NSMCE3, SMC5 and SLF2 and other genes whose functional interactions with Smc5/6 are discussed in the text, including BTR genes (BLM, TOP3A, RMI1/2, POLE1/2) and FA genes. Images in a reproduced under a Creative Commons license CC BY 4.0 from Payne et al. (top) and Atkins et al. (bottom). Image in b adapted from Wikimedia (https://commons.wikimedia.org/wiki/Human_body_diagrams).
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