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Suppressor mutation analysis combined with 3D modeling explains cohesin’s capacity to hold and release DNA
Contributed by Mitsuhiro Yanagida, April 17, 2018 (sent for review March 9, 2018; reviewed by David M. Glover, James E. Haber, and Aaron F. Straight)

Significance
The heterodimeric cohesin SMC complex embraces duplex DNA and is associated with Rad21, which is cleaved in mitotic anaphase by a protease called separase/Cut1. Upon Rad21 cleavage, chromosomal DNAs are released from cohesin and segregated. We identified extragenic suppressors for separase and cohesin temperature-sensitive (ts) mutants using whole-genome sequencing and made the surprising discovery that cleavage of Rad21 is largely dispensable if suppressor causes physical disorders of cohesin interfaces among essential subunits. The predicted disorders provide insights into a DNA “hold-and-release” model in which hinge and head of SMC subunits are proximal to form arched coiled coils that close or open by their orientation. The model is distinct from the “ring” model and may promote further study.
Abstract
Cohesin is a fundamental protein complex that holds sister chromatids together. Separase protease cleaves a cohesin subunit Rad21/SCC1, causing the release of cohesin from DNA to allow chromosome segregation. To understand the functional organization of cohesin, we employed next-generation whole-genome sequencing and identified numerous extragenic suppressors that overcome either inactive separase/Cut1 or defective cohesin in the fission yeast Schizosaccharomyces pombe. Unexpectedly, Cut1 is dispensable if suppressor mutations cause disorders of interfaces among essential cohesin subunits Psm1/SMC1, Psm3/SMC3, Rad21/SCC1, and Mis4/SCC2, the crystal structures of which suggest physical and functional impairment at the interfaces of Psm1/3 hinge, Psm1 head–Rad21, or Psm3 coiled coil–Rad21. Molecular-dynamics analysis indicates that the intermolecular β-sheets in the cohesin hinge of cut1 suppressor mutants remain intact, but a large mobility change occurs at the coiled coil bound to the hinge. In contrast, suppressors of rad21-K1 occur in either the head ATPase domains or the Psm3 coiled coil that interacts with Rad21. Suppressors of mis4-G1326E reside in the head of Psm3/1 or the intragenic domain of Mis4. These may restore the binding of cohesin to DNA. Evidence is provided that the head and hinge of SMC subunits are proximal, and that they coordinate to form arched coils that can hold or release DNA by altering the angles made by the arched coiled coils. By combining molecular modeling with suppressor sequence analysis, we propose a cohesin structure designated the “hold-and-release” model, which may be considered as an alternative to the prevailing “ring” model.
Footnotes
↵1X.X., R.K., and N.N. contributed equally to this work.
- ↵2To whom correspondence should be addressed. Email: myanagid{at}gmail.com.
Author contributions: X.X., R.K., N.N., C.T., and M.Y. designed research; X.X., R.K., N.N., and L.W. performed research; X.X. and R.K. analyzed data; and X.X., R.K., N.N., C.T., and M.Y. wrote the paper.
Reviewers: D.M.G., University of Cambridge; J.E.H., Brandeis University; and A.F.S., Stanford University.
The authors declare no conflict of interest.
Data deposition: The sequencing data reported in this paper have been deposited in the National Center for Biotechnology Information BioProject database (accession number PRJNA450289).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1803564115/-/DCSupplemental.
- Copyright © 2018 the Author(s). Published by PNAS.
This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
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