The SMC5/6 complex: folding chromosomes back into shape when genomes take a break

Abstract

High-level folding of chromatin is a key determinant of the shape and functional state of chromosomes. During cell division, structural maintenance of chromosome (SMC) complexes such as condensin and cohesin ensure large-scale folding of chromatin into visible chromosomes. In contrast, the SMC5/6 complex plays more local and context-specific roles in the structural organization of interphase chromosomes with important implications for health and disease. Recent advances in single-molecule biophysics and cryo-electron microscopy revealed key insights into the architecture of the SMC5/6 complex and how interactions connecting the complex to chromatin components give rise to its unique repertoire of interphase functions. In this review, we provide an integrative view of the features that differentiates the SMC5/6 complex from other SMC enzymes and how these enable dramatic reorganization of DNA folding in space during DNA repair reactions and other genome transactions. Finally, we explore the mechanistic basis for the dynamic targeting of the SMC5/6 complex to damaged chromatin and its crucial role in human health.

Graphical Abstract

Figure 1.

(A) Schematic representation of the functional domains, folding, and dimerization states of SMC5 and SMC6 proteins. Shown on the left is a cartoon representation of the domain organization of a typical SMC protein in its unfolded state. The middle section of the panel depicts the same SMC monomer in its mature state. Specifically, the newly synthesized SMC protein initially fold back on itself (in a manner analogous to a conventional hairpin) to create a functional coiled-coil arm and ATPase head domain. This allows the folded/mature protein to dimerize with another SMC family member using their respective hinge domains. The right side of the panel shows the SMC5/6 dimer in cartoon and structural representations. (B) Cryo-EM composite structure and molecular graphics representation of the SMC5/6 complex and its individual subunits (170) edited in UCFC ChimeraX. The hinge, coiled-coil arm and ATPase head domains are labelled on the right-hand side of the SMC5 structure. Individual subunits/subcomplexes are shown in different color schemes to facilitate visualization; SMC5, violet; SMC6, wheat/beige; NSE1, light green; NSE2, pink; NSE3, dark green; NSE4, blue; NSE5, peach; and NSE6, maroon (170). The model shown in this panel corresponds to the Saccharomyces cerevisiae enzyme and is derived from data of Hallett and collaborator (58), as deposited in the RCSB database (PDB: 7QCD). (C) Cryo-EM structure of the budding yeast SMC5/6 dimer and NSE5/NSE6 subcomplex interacting with the SMC5/SMC6-head neck region. The lower portion of the panel is derived from the SMC5/6–8mer complex structure of Li and colleagues (72), as deposited in the RCSB database (PDB: 8T8F).

Figure 2.

Landscape of the SMC5/6 complex functions and phenotypes. Each section of the figure depicts a distinct cellular function (DNA repair/telomere) and/or disease state associated with the SMC5/6 holoenzyme (viral infection, rare genetic diseases, and cancer). Abbreviations: HR, homologous recombination; RF, replication fork; ALT, alternative lengthening of telomeres; MV, mosaic variegated; LICS, lung disease immunodeficiency and chromosome breakage syndrome; HBV, hepatitis B virus; HIV, human immunodeficiency virus. See text for a detailed description of the molecular pathways and diseases presented in this figure.

Figure 3.

A 5-step model depicting the catalytic cycle of the SMC5/6 complex on chromosomal DNA substrates. Step 1 shows the differential nucleic acid binding patterns of the SMC5/6 complex. Examples of relevant types of nucleic acid substrates (ssDNA, dsDNA, Holliday junctions, and branched DNA structures) are shown. The schematic illustration of the SMC5/6 complex binding to DNA represents a generic association and no specific mode of DNA binding should be inferred from the illustration (see text for more details). Step 2 illustrates the movement dynamics of the complex along DNA. After its initial binding to DNA, the SMC5/6 complex translocates on double-stranded DNA to scan for a relevant substrate. The SMC5/6 complex is enriched at junction DNA where it undergoes dimerization. Note that while dimerization of the complex has been established on undamaged DNA (28) and appears likely at sites of DNA damage, it nevertheless remains to be formally demonstrated in the context of DNA lesions. Step 3 shows the nature of DNA compaction carried out by the SMC5/6 complex. DNA compaction likely occurs through loop extrusion mediated by the dimeric complex. Step 4 proposes downstream effects of the SMC5/6 complex after DNA compaction is completed. Among these effects, we envision that the compacted DNA creates a protective environment as well as an effective platform for the recruitment of downstream effectors for DNA repair. Step 5 depicts the unloading of the SMC5/6 complex from the compacted chromatin. See main text for a more detailed explanation of this hypothetical model.