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Sequential primed kinases create a damage-responsive phosphodegron on Eco1.

Sister-chromatid cohesion is established during S phase when Eco1 acetylates cohesin. In budding yeast, Eco1 activity falls after S phase due to Cdk1-dependent phosphorylation, which triggers ubiquitination by SCF(Cdc4). We show here that Eco1 degradation requires the sequential actions of Cdk1 and two additional kinases, Cdc7-Dbf4 and the GSK-3 homolog Mck1. These kinases recognize motifs primed by previous phosphorylation, resulting in an ordered sequence of three phosphorylation events on Eco1. Only the latter two phosphorylation sites are spaced correctly to bind Cdc4, resulting in strict discrimination between phosphates added by Cdk1 and by Cdc7. Inhibition of Cdc7 by the DNA damage response prevents Eco1 destruction, allowing establishment of cohesion after S phase. This elaborate regulatory system, involving three independent kinases and stringent substrate selection by a ubiquitin ligase, enables robust control of cohesion establishment during normal growth and after stress.

Pubmed ID: 23314252


  • Lyons NA
  • Fonslow BR
  • Diedrich JK
  • Yates JR
  • Morgan DO


Nature structural & molecular biology

Publication Data

February 5, 2013

Associated Grants

  • Agency: NIGMS NIH HHS, Id: P41-GM103533
  • Agency: NCRR NIH HHS, Id: P41-RR011823
  • Agency: NIGMS NIH HHS, Id: R01 GM069901
  • Agency: NIGMS NIH HHS, Id: R01-GM069901
  • Agency: NICHD NIH HHS, Id: T32 HD007470

Mesh Terms

  • Acetyltransferases
  • Blotting, Western
  • CDC2 Protein Kinase
  • Cell Cycle Proteins
  • Chromatids
  • Chromosomal Proteins, Non-Histone
  • DNA Damage
  • F-Box Proteins
  • Fluorescence Polarization
  • Glycogen Synthase Kinase 3
  • Mass Spectrometry
  • Nuclear Proteins
  • Phosphorylation
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases
  • Proteolysis
  • S Phase
  • Saccharomyces cerevisiae Proteins
  • Substrate Specificity
  • Ubiquitin-Protein Ligases