The Kinetochore Receptor for the Cohesin Loading Complex

Stephen M Hinshaw,Vasso Makrantoni,Stephen C Harrison,Adèle L Marston

doi:10.1016/j.cell.2017.08.017

Stephen M Hinshaw, Vasso Makrantoni + Show 2 more

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https://doi.org/10.1016/j.cell.2017.08.017

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Abstract

SummaryThe ring-shaped cohesin complex brings together distant DNA domains to maintain, express, and segregate the genome. Establishing specific chromosomal linkages depends on cohesin recruitment to defined loci. One such locus is the budding yeast centromere, which is a paradigm for targeted cohesin loading. The kinetochore, a multiprotein complex that connects centromeres to microtubules, drives the recruitment of high levels of cohesin to link sister chromatids together. We have exploited this system to determine the mechanism of specific cohesin recruitment. We show that phosphorylation of the Ctf19 kinetochore protein by a conserved kinase, DDK, provides a binding site for the Scc2/4 cohesin loading complex, thereby directing cohesin loading to centromeres. A similar mechanism targets cohesin to chromosomes in vertebrates. These findings represent a complete molecular description of targeted cohesin loading, a phenomenon with wide-ranging importance in chromosome segregation and, in multicellular organisms, transcription regulation.

Highlights

Genome maintenance, expression, and transmission depend on organization of chromosomes into functional domains
dependent kinase (DDK) Phosphorylates Ctf19-Mcm21 Several observations suggest that DDK phosphorylates a component of the Ctf19 complex (Figure 1A) and that this signal recruits Scc2 to centromeres
To confirm that phosphate transfer to Ctf19-Mcm21 depended on the catalytic activity of Cdc7 and not a co-purifying kinase, we purified an ATP analog (PP1)-sensitive mutant of DDK (Wan et al, 2006)

Summary

Introduction

Expression, and transmission depend on organization of chromosomes into functional domains. At the heart of this organization, in both prokaryotes and eukaryotes, are protein complexes in the structural maintenance of chromosomes (SMC) family: cohesin, condensin, and SMC5/6 (Uhlmann, 2016). These complexes must be targeted to specific regions of the chromosome, including areas of damage, transcriptional units, and centromeres. A separate and broadly conserved two-protein complex called Scc2/4 in yeast and NIPBL/Mau in humans loads cohesin onto chromosomes (Ciosk et al, 2000). The dual role of cohesin loading in chromosome segregation and transcription regulation (Fay et al, 2011) makes determining molecular pathways for targeted cohesin loading an issue of broad interest

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