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Published April 19, 2001 | public
Journal Article

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 (M_r 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 (t_(1/2)≈ 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 ubr1Δ cells, which lack the N-end rule pathway, we found a highly increased frequency of chromosome loss. The bulk of increased chromosome loss in ubr1Δ 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.

Additional Information

© 2001 Macmillan Magazines Ltd. Received 20 November 2000; Accepted 17 January 2001. We are grateful to G. Turner, H.-R. Wang, F. Du, V. Ellison, A. Murray, D. Morgan, B. Stillman and P. Hieter for strains and plasmids. We thank M. Budd, W. Shuo and members of the Varshavsky laboratory, particularly F. Du and G. Turner, for helpful discussions. This work was supported by grants to A.V. from the NIH. H.R. is a Fellow of the Leukemia and Lymphoma Society. K.N. was supported by the Austrian Industrial Research Promotion Fund.

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