Anaphase initiation is regulated by antagonistic ubiquitination and deubiquitination activities

Frank Stegmeier, Michael Rape, Viji M. Draviam, Grzegorz Nalepa, Mathew E. Sowa, Xiaolu L. Ang, E. Robert McDonald, Mamie Z. Li, Gregory J. Hannon, Peter K. Sorger, Marc W. Kirschner (), J. Wade Harper () and Stephen J. Elledge ()
Additional contact information
Frank Stegmeier: Howard Hughes Medical Institute, Harvard Partners Center for Genetics and Genomics, and
Michael Rape: Harvard Medical School, Boston, Massachusetts 02115, USA
Viji M. Draviam: Harvard Medical School, Boston, Massachusetts 02115, USA
Grzegorz Nalepa: Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA
Mathew E. Sowa: Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA
Xiaolu L. Ang: Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA
E. Robert McDonald: Howard Hughes Medical Institute, Harvard Partners Center for Genetics and Genomics, and
Mamie Z. Li: Howard Hughes Medical Institute, Harvard Partners Center for Genetics and Genomics, and
Gregory J. Hannon: Cold Spring Harbor Laboratory, Watson School of Biological Sciences, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA
Peter K. Sorger: Harvard Medical School, Boston, Massachusetts 02115, USA
Marc W. Kirschner: Harvard Medical School, Boston, Massachusetts 02115, USA
J. Wade Harper: Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA
Stephen J. Elledge: Howard Hughes Medical Institute, Harvard Partners Center for Genetics and Genomics, and

Nature, 2007, vol. 446, issue 7138, 876-881

Abstract: Abstract The spindle checkpoint prevents chromosome mis-segregation by delaying sister chromatid separation until all chromosomes have achieved bipolar attachment to the mitotic spindle. Its operation is essential for accurate chromosome segregation, whereas its dysregulation can contribute to birth defects and tumorigenesis. The target of the spindle checkpoint is the anaphase-promoting complex (APC), a ubiquitin ligase that promotes sister chromatid separation and progression to anaphase. Using a short hairpin RNA screen targeting components of the ubiquitin-proteasome pathway in human cells, we identified the deubiquitinating enzyme USP44 (ubiquitin-specific protease 44) as a critical regulator of the spindle checkpoint. USP44 is not required for the initial recognition of unattached kinetochores and the subsequent recruitment of checkpoint components. Instead, it prevents the premature activation of the APC by stabilizing the APC-inhibitory Mad2–Cdc20 complex. USP44 deubiquitinates the APC coactivator Cdc20 both in vitro and in vivo, and thereby directly counteracts the APC-driven disassembly of Mad2–Cdc20 complexes (discussed in an accompanying paper). Our findings suggest that a dynamic balance of ubiquitination by the APC and deubiquitination by USP44 contributes to the generation of the switch-like transition controlling anaphase entry, analogous to the way that phosphorylation and dephosphorylation of Cdk1 by Wee1 and Cdc25 controls entry into mitosis.

Date: 2007
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DOI: 10.1038/nature05694

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