title: Cohesin-dependent association of scc2/4 with the centromere initiates pericentromeric cohesion establishment.
abstract: Cohesin is a conserved ring-shaped multiprotein complex that participates in chromosome segregation, DNA repair, and transcriptional regulation [1, 2]. Cohesin loading onto chromosomes universally requires the Scc2/4 "loader" complex (also called NippedBL/Mau2), mutations in which cause the developmental disorder Cornelia de Lange syndrome in humans [1-9]. Cohesin is most concentrated in the pericentromere, the region surrounding the centromere [10-15]. Enriched pericentromeric cohesin requires the Ctf19 kinetochore subcomplex in budding yeast [16-18]. Here, we uncover the spatial and temporal determinants for Scc2/4 centromere association. We demonstrate that the critical role of the Ctf19 complex is to enable Scc2/4 association with centromeres, through which cohesin loads and spreads onto the adjacent pericentromere. We show that, unexpectedly, Scc2 association with centromeres depends on cohesin itself. The absence of the Scc1/Mcd1/Rad21 cohesin subunit precludes Scc2 association with centromeres from anaphase until late G1. Expression of SCC1 is both necessary and sufficient for the binding of cohesin to its loader, the association of Scc2 with centromeres, and cohesin loading. We propose that cohesin triggers its own loading by enabling Scc2/4 to connect with chromosomal landmarks, which at centromeres are specified by the Ctf19 complex. Overall, our findings provide a paradigm for the spatial and temporal control of cohesin loading.
authors.affiliation: The Wellcome Trust Centre for Cell Biology, School of Biological Sciences, Michael Swann Building, Mayfield Road, Edinburgh EH9 3JR, UK.
authors.forename: Josefin
authors.initials: J
authors.lastname: Fernius
authors.forename: Olga O
authors.initials: OO
authors.lastname: Nerusheva
authors.forename: Stefan
authors.initials: S
authors.lastname: Galander
authors.forename: Flavia de Lima
authors.initials: Fde L
authors.lastname: Alves
authors.forename: Juri
authors.initials: J
authors.lastname: Rappsilber
authors.forename: Adele L
authors.initials: AL
authors.lastname: Marston
mesh_terms: D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002503:Centromere / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D005434:Flow Cytometry; D047468:Immunoprecipitation; D018386:Kinetochores / Q000378:metabolism*; D013058:Mass Spectrometry; D046912:Multiprotein Complexes / Q000302:isolation & purification / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D015003:Yeasts; D000097722:Cohesins
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D003598:Cytoskeletal Proteins; D017931:DNA Primers; D046912:Multiprotein Complexes; D029701:Saccharomyces cerevisiae Proteins; D000097722:Cohesins; C477822:CTF19 protein, S cerevisiae; C410592:SCC2 protein, S cerevisiae; C410593:SCC4 protein, S cerevisiae