Abstract
Cohesin has essential roles in chromosome structure, segregation and repair. Cohesin binding to chromosomes is catalyzed by the cohesin loader, Mis4 in fission yeast. How cells fine tune cohesin deposition is largely unknown. Here, we provide evidence that Mis4 activity is regulated by phosphorylation of its cohesin substrate. A genetic screen for negative regulators of Mis4 yielded a CDK called Pef1, whose closest human homologue is CDK5. Inhibition of Pef1 kinase activity rescued cohesin loader deficiencies. In an otherwise wild-type background, Pef1 ablation stimulated cohesin binding to its regular sites along chromosomes while ablating Protein Phosphatase 4 had the opposite effect. Pef1 and PP4 control the phosphorylation state of the cohesin kleisin Rad21. The CDK phosphorylates Rad21 on Threonine 262. Pef1 ablation, non-phosphorylatable Rad21-T262 or mutations within a Rad21 binding domain of Mis4 alleviated the effect of PP4 deficiency. Such a CDK/PP4-based regulation of cohesin loader activity could provide an efficient mechanism for translating cellular cues into a fast and accurate cohesin response.
Highlights
Cohesin is a central player in chromosome biology
The core cohesin complex is made of two long Structural Maintenance of Chromosome (SMC) proteins (Psm1 and Psm3 in fission yeast) whose ATPase heads are bridged by a kleisin subunit called Scc1/Mcd1/Rad21
Cohesin is involved in a wide range of cellular functions at all stages of the cell cycle, implying a tight control by the cell machinery
Summary
Cohesin is a central player in chromosome biology. Cohesin is an ATPase-driven molecular machine able to tether DNA by topological entrapment (Ivanov and Nasmyth, 2005; Haering et al, 2008; Gligoris et al, 2014). The core cohesin complex is made of two long Structural Maintenance of Chromosome (SMC) proteins (Psm and Psm in fission yeast) whose ATPase heads are bridged by a kleisin subunit called Scc1/Mcd1/Rad. The cohesin complex ensures proper chromosome segregation by holding sister chromatids together from DNA replication and until their segregation at anaphase onset. Cohesin is essential for DNA repair and the formation of DNA loops that shape chromosome architecture and impinge on gene regulation (Makrantoni and Marston, 2018; van Ruiten and Rowland, 2018; ArzateMejıa et al, 2018). Cohesin is central to many biological processes, emphasizing the importance of understanding its regulation
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