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      The structure of the cohesin ATPase elucidates the mechanism of SMC–kleisin ring opening

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          Abstract

          Genome regulation requires control of chromosomal organization by SMC–kleisin complexes. The cohesin complex contains the Smc1 and Smc3 subunits which associate with the kleisin Scc1 to form a ring-shaped complex that can topologically engage chromatin to regulate chromatin structure. Release from chromatin involves opening of the ring at the Smc3–Scc1 interface in a reaction that is controlled by acetylation and engagement of the Smc ATPase head domains. To understand the underlying molecular mechanisms, we have determined the 3.2 Å cryo-EM structure of the ATPγS-bound, hetero-trimeric cohesin ATPase head module, and the 2.1 Å crystal structure of a nucleotide-free Smc1–Scc1 subcomplex from Saccharomyces cerevisiae and Chaetomium thermophilium. We found that ATP-binding and Smc1–Smc3 heterodimerization promote conformational changes within the ATPase which are transmitted to the Smc coiled-coil domains. Remodeling of the coiled-coil domain of Smc3 abrogates the binding surface for Scc1 thus leading to ring opening at the Smc3–Scc1 interface.

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          Most cited references 42

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          Cleavage of cohesin by the CD clan protease separin triggers anaphase in yeast.

          In eukaryotic cells, replicated DNA strands remain physically connected until their segregation to opposite poles of the cell during anaphase. This "sister chromatid cohesion" is essential for the alignment of chromosomes on the mitotic spindle during metaphase. Cohesion depends on the multisubunit cohesin complex, which possibly forms the physical bridges connecting sisters. Proteolytic cleavage of cohesin's Sccl subunit at the metaphase to anaphase transition is essential for sister chromatid separation and depends on a conserved protein called separin. We show here that separin is a cysteine protease related to caspases that alone can cleave Sccl in vitro. Cleavage of Sccl in metaphase arrested cells is sufficient to trigger the separation of sister chromatids and their segregation to opposite cell poles.
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            Eco1-dependent cohesin acetylation during establishment of sister chromatid cohesion.

            Replicated chromosomes are held together by the chromosomal cohesin complex from the time of their synthesis in S phase onward. This requires the replication fork-associated acetyl transferase Eco1, but Eco1's mechanism of action is not known. We identified spontaneous suppressors of the thermosensitive eco1-1 allele in budding yeast. An acetylation-mimicking mutation of a conserved lysine in cohesin's Smc3 subunit makes Eco1 dispensable for cell growth, and we show that Smc3 is acetylated in an Eco1-dependent manner during DNA replication to promote sister chromatid cohesion. A second set of eco1-1 suppressors inactivate the budding yeast ortholog of the cohesin destabilizer Wapl. Our results indicate that Eco1 modifies cohesin to stabilize sister chromatid cohesion in parallel with a cohesion establishment reaction that is in principle Eco1-independent.
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              A molecular determinant for the establishment of sister chromatid cohesion.

              Chromosome segregation, transcriptional regulation, and repair of DNA double-strand breaks require the cohesin protein complex. Cohesin holds the replicated chromosomes (sister chromatids) together to mediate sister chromatid cohesion. The mechanism of how cohesion is established is unknown. We found that in budding yeast, the head domain of the Smc3p subunit of cohesin is acetylated by the Eco1p acetyltransferase at two evolutionarily conserved residues, promoting the chromatin-bound cohesin to tether sister chromatids. Smc3p acetylation is induced in S phase after the chromatin loading of cohesin and is suppressed in G(1) and G(2)/M. Smc3 head acetylation and its cell cycle regulation provide important insights into the biology and mechanism of cohesion establishment.
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                Author and article information

                Journal
                101186374
                Nat Struct Mol Biol
                Nat. Struct. Mol. Biol.
                Nature structural & molecular biology
                1545-9993
                1545-9985
                14 January 2020
                17 February 2020
                March 2020
                17 August 2020
                : 27
                : 3
                : 233-239
                Affiliations
                [1 ]European Molecular Biology Laboratory, Grenoble, France
                [2 ]European Molecular Biology Laboratory, Structural and Computational Biology Unit, Heidelberg, Germany
                [3 ]Leicester Institute of Structural and Chemical Biology, Department of Molecular and Cell Biology, University of Leicester, United Kingdom
                [4 ]MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
                Author notes
                [* ]Correspondence and requests for materials should be addressed to D.P. ( daniel.panne@ 123456le.ac.uk ) or K.W.M. ( kmuir@ 123456mrc-lmb.cam.ac.uk ).
                Article
                EMS85447
                10.1038/s41594-020-0379-7
                7100847
                32066964

                Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                Categories
                Article

                Molecular biology

                genome regulation, cryoem, smc, chromatin folding, cohesin

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