Inducible Degradation of the Human SMC5/6 Complex Reveals an Essential Role Only during Interphase

• Published in: Cell reports (Cambridge) 2020-04, Vol.31 (3), p.107533-107533, Article 107533
• Main Authors: Venegas, Andrés Bueno, Natsume, Toyoaki, Kanemaki, Masato, Hickson, Ian D.
• Format: Article
• Language: English
• Subjects: Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line; Cell Proliferation - physiology; Cell Survival - physiology; Chromosomal Proteins, Non-Histone - genetics; Chromosomal Proteins, Non-Histone - metabolism; Chromosome Segregation; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; DNA Damage; Genomic Instability; HCT116 Cells; Humans; Interphase - physiology; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.107533

The cohesin- and condensin-related SMC5/6 complex has largely been studied in the context of DNA repair. Nevertheless, SMC5/6 has an undefined essential function even in the absence of cellular stress. Through the use of an auxin-inducible degradation system for rapidly depleting subunits of the SMC5/6 complex, we show that SMC5/6 is essential for viability in cancer-derived and normal human cells. Impairment of SMC5/6 function is associated with spontaneous induction of DNA damage, p53 activation, cell-cycle arrest, and senescence, as well as an increased frequency of various mitotic chromosome segregation abnormalities. However, we show that this chromosome missegregation is apparent only when SMC5/6 function is impaired during the preceding S and G2 phases. In contrast, degradation of SMC5/6 immediately prior to mitotic entry has little or no impact on the fidelity of chromosome segregation, highlighting the importance of the complex during interphase in order to ensure faithful sister chromatid disjunction. [Display omitted] •Subunits of the SMC5/6 complex are essential for mitotic growth in human cells•Impaired SMC5/6 function is associated with increased mitotic aberrations•SMC5/6 is required for proper disjunction of repetitive sequences in mitosis•Mitotic defects following SMC5/6 loss are due to functions in interphase Venegas et al. employ an auxin-inducible degron system for different subunits of the SMC5/6 complex to interrogate the short- and long-term effects of SMC5/6 impairment in human cells. Degradation of SMC5/6’s subunits at different cell cycle stages places the essential role of the complex during S phase.