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Phosphorylation-enabled binding of SGO1–PP2A to cohesin protects sororin and centromeric cohesion during mitosis

Nature Cell Biology volume 15, pages 40–49 (2013)Cite this article

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An Erratum to this article was published on 01 February 2013

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Abstract

Timely dissolution of sister-chromatid cohesion in mitosis ensures accurate chromosome segregation to guard against aneuploidy and tumorigenesis. The complex of shugoshin and protein phosphatase 2A (SGO1–PP2A) protects cohesin at centromeres from premature removal by mitotic kinases and WAPL in prophase. Here we address the regulation and mechanism of human SGO1 in centromeric cohesion protection, and show that cyclin-dependent kinase (CDK)-mediated, mitosis-specific phosphorylation of SGO1 activates its cohesion-protection function and enables its direct binding to cohesin. The phospho-SGO1-bound cohesin complex contains PP2A, PDS5 and hypophosphorylated sororin, but lacks WAPL. Expression of non-phosphorylatable sororin bypasses the requirement for SGO1–PP2A in centromeric cohesion. Thus, mitotic phosphorylation of SGO1 targets SGO1–PP2A to cohesin, promotes dephosphorylation of PDS5-bound sororin and protects centromeric cohesin from WAPL. PP2A-orchestrated, site-selective dephosphorylation of cohesin and its regulators underlies centromeric cohesion protection.

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Figure 1: Human SGO1 undergoes CDK-dependent phosphorylation at Thr 346 during mitosis.
Figure 2: SGO1 T346A localizes to centromeres, but is defective in sister-chromatid cohesion.
Figure 3: SGO1 T346A localizes to centromeres and binds to PP2A.
Figure 4: SGO1 Thr 346 phosphorylation promotes its binding to cohesin.
Figure 5: SGO1–PP2A maintains cohesin-bound sororin in a hypophosphorylated state to counteract WAPL.
Figure 6: Sororin is required for the ectopic arm cohesion induced by SGO1 overexpression.
Figure 7: Expression of non-phosphorylatable sororin bypasses the requirement for SGO1–PP2A in cohesion protection.
Figure 8: Sororin dissociation from mitotic chromosomes requires CDK1.

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Change history

  • 20 December 2012

    In the version of this Article initially published online and in print, the protein WAPL was mistakenly written as 'WAP1'.

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Acknowledgements

We thank Y. Li and the Protein Chemistry Core at UT Southwestern Medical Center for mass spectrometry analysis of phospho-SGO1. We also thank J. Chen (Oklahoma Medical Research Foundation, USA) for making the sororin antibody and J-M. Peters (Research Institute of Molecular Pathology, Vienna, Austria) for providing the phospho-S1224-SA2 antibody. S.R. was financially supported by grant RR016478 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and is a Pew Scholar in the Biomedical Sciences. H.Y. is an Investigator with the Howard Hughes Medical Institute and is supported by grants from the Welch Foundation (I-1441) and the Cancer Prevention Research Institute of Texas (RP110465).

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Authors and Affiliations

  1. Department of Pharmacology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, Texas 75390, USA

    Hong Liu & Hongtao Yu

  2. Program in Cell Cycle and Cancer Biology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA

    Susannah Rankin

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H.L. designed and performed all experiments and analysed the data. H.Y. supervised the project and analysed the data. S.R. provided key reagents and analysed the data. H.L. and H.Y. wrote the paper.

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Correspondence to Hongtao Yu.

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Liu, H., Rankin, S. & Yu, H. Phosphorylation-enabled binding of SGO1–PP2A to cohesin protects sororin and centromeric cohesion during mitosis. Nat Cell Biol 15, 40–49 (2013). https://doi.org/10.1038/ncb2637

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