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Degradation of a cohesin subunit by the N-end rule pathway is essential for chromosome stability.

Cohesion between sister chromatids is established during DNA replication and depends on a protein complex called cohesin. At the metaphase-anaphase transition in the yeast Saccharomyces cerevisiae, the ESP1-encoded protease separin cleaves SCC1, a subunit of cohesin with a relative molecular mass of 63,000 (Mr 63K). The resulting 33K carboxy-terminal fragment of SCC1 bears an amino-terminal arginine-a destabilizing residue in the N-end rule. Here we show that the SCC1 fragment is short-lived (t1/2 approximately 2 min), being degraded by the ubiquitin/proteasome-dependent N-end rule pathway. Overexpression of a long-lived derivative of the SCC1 fragment is lethal. In ubr1Delta cells, which lack the N-end rule pathway, we found a highly increased frequency of chromosome loss. The bulk of increased chromosome loss in ubr1Delta cells is caused by metabolic stabilization of the ESP1-produced SCC1 fragment. This fragment is the first physiological substrate of the N-end rule pathway that is targeted through its N-terminal residue. A number of yeast proteins bear putative cleavage sites for the ESP1 separin, suggesting other physiological substrates and functions of the N-end rule pathway.

Pubmed ID: 11309624

Authors

  • Rao H
  • Uhlmann F
  • Nasmyth K
  • Varshavsky A

Journal

Nature

Publication Data

April 19, 2001

Associated Grants

None

Mesh Terms

  • Anaphase
  • Arginine
  • Cell Cycle Proteins
  • Cell Division
  • Chromatids
  • Chromosomal Proteins, Non-Histone
  • Chromosome Segregation
  • Chromosomes, Fungal
  • Cysteine Endopeptidases
  • Dipeptides
  • Endopeptidases
  • Fungal Proteins
  • Half-Life
  • Ligases
  • Multienzyme Complexes
  • Nuclear Proteins
  • Peptide Fragments
  • Phosphoproteins
  • Proteasome Endopeptidase Complex
  • Recombinant Fusion Proteins
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Separase
  • Ubiquitin-Protein Ligases
  • Ubiquitins