Skp, Cullin, F-box (SCF)-Met30 and SCF-Cdc4-Mediated Proteolysis of CENP-A Prevents Mislocalization of CENP-A for Chromosomal Stability in Budding Yeast

Autoři: Wei-Chun Au aff001;  Tianyi Zhang aff001;  Prashant K. Mishra aff001;  Jessica R. Eisenstatt aff001;  Robert L. Walker aff001;  Josefina Ocampo aff002;  Anthony Dawson aff001;  Jack Warren aff001;  Michael Costanzo aff003;  Anastasia Baryshnikova aff004;  Karin Flick aff005;  David J. Clark aff002;  Paul S. Meltzer aff001;  Richard E. Baker aff006;  Chad Myers aff007;  Charles Boone aff003;  Peter Kaiser aff005;  Munira A. Basrai aff001
Působiště autorů: Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States of America aff001;  Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States of America aff002;  Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada aff003;  Calico Life Sciences LLC, South San Francisco, CA, United States of America aff004;  Department of Biological Chemistry, College of Medicine, University of California, Irvine, CA, United States of America aff005;  Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, United States of America aff006;  Department of Computer Science and Engineering, University of Minnesota-Twin Cities, Minneapolis, MN, United States of America aff007
Vyšlo v časopise: Skp, Cullin, F-box (SCF)-Met30 and SCF-Cdc4-Mediated Proteolysis of CENP-A Prevents Mislocalization of CENP-A for Chromosomal Stability in Budding Yeast. PLoS Genet 16(2): e32767. doi:10.1371/journal.pgen.1008597
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008597


Restricting the localization of the histone H3 variant CENP-A (Cse4 in yeast, CID in flies) to centromeres is essential for faithful chromosome segregation. Mislocalization of CENP-A leads to chromosomal instability (CIN) in yeast, fly and human cells. Overexpression and mislocalization of CENP-A has been observed in many cancers and this correlates with increased invasiveness and poor prognosis. Yet genes that regulate CENP-A levels and localization under physiological conditions have not been defined. In this study we used a genome-wide genetic screen to identify essential genes required for Cse4 homeostasis to prevent its mislocalization for chromosomal stability. We show that two Skp, Cullin, F-box (SCF) ubiquitin ligases with the evolutionarily conserved F-box proteins Met30 and Cdc4 interact and cooperatively regulate proteolysis of endogenous Cse4 and prevent its mislocalization for faithful chromosome segregation under physiological conditions. The interaction of Met30 with Cdc4 is independent of the D domain, which is essential for their homodimerization and ubiquitination of other substrates. The requirement for both Cdc4 and Met30 for ubiquitination is specifc for Cse4; and a common substrate for Cdc4 and Met30 has not previously been described. Met30 is necessary for the interaction between Cdc4 and Cse4, and defects in this interaction lead to stabilization and mislocalization of Cse4, which in turn contributes to CIN. We provide the first direct link between Cse4 mislocalization to defects in kinetochore structure and show that SCF-mediated proteolysis of Cse4 is a major mechanism that prevents stable maintenance of Cse4 at non-centromeric regions, thus ensuring faithful chromosome segregation. In summary, we have identified essential pathways that regulate cellular levels of endogenous Cse4 and shown that proteolysis of Cse4 by SCF-Met30/Cdc4 prevents mislocalization and CIN in unperturbed cells.

Klíčová slova:

Cell cycle and cell division – Galactose – Glucose – Histones – Chromatin – Chromosomes – Proteolysis – Ubiquitination


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