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Multiple mechanisms determine the order of APC/C substrate degradation in mitosis.

Lu D, Hsiao JY, Davey NE, Van Voorhis VA, Foster SA, Tang C, Morgan DO - J. Cell Biol. (2014)

Bottom Line: The spindle assembly checkpoint delays the onset of Clb5 degradation but does not influence securin degradation.The degradation of securin and Dbf4 is delayed by Cdk1-dependent phosphorylation near their Cdc20-binding sites.Thus, a remarkably diverse array of mechanisms generates robust ordering of APC/C(Cdc20) substrate destruction.

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Affiliation: Department of Physiology and Department of Biochemistry and Biophysics and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158.

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APC/C substrate degradation timing in yeast and mammalian cells. (A) Summary of the regulatory events leading to the metaphase–anaphase transition in yeast and mammalian cells, and the mechanisms that determine the timing and order of APC/CCdc20 substrate degradation in wild-type cells. (B) In yeast, defects in SAC function cause earlier Clb5 destruction but do not affect the timing of securin destruction. In contrast, in mammalian cells, SAC defects result in earlier cyclin A and securin destruction and anaphase onset. (C) In a prolonged SAC arrest, securin is stable, whereas Cks1 and the ABBA motif promote slow degradation of Clb5 and cyclin A. The diagrams in this figure are based on the current work and many previous studies (J. Pines, personal communication; Clute and Pines, 1999; den Elzen and Pines, 2001; Geley et al., 2001; Hagting et al., 2002; Wolthuis et al., 2008; Di Fiore and Pines, 2010; Shindo et al., 2012; Yaakov et al., 2012; Collin et al., 2013; Dick and Gerlich, 2013).
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fig7: APC/C substrate degradation timing in yeast and mammalian cells. (A) Summary of the regulatory events leading to the metaphase–anaphase transition in yeast and mammalian cells, and the mechanisms that determine the timing and order of APC/CCdc20 substrate degradation in wild-type cells. (B) In yeast, defects in SAC function cause earlier Clb5 destruction but do not affect the timing of securin destruction. In contrast, in mammalian cells, SAC defects result in earlier cyclin A and securin destruction and anaphase onset. (C) In a prolonged SAC arrest, securin is stable, whereas Cks1 and the ABBA motif promote slow degradation of Clb5 and cyclin A. The diagrams in this figure are based on the current work and many previous studies (J. Pines, personal communication; Clute and Pines, 1999; den Elzen and Pines, 2001; Geley et al., 2001; Hagting et al., 2002; Wolthuis et al., 2008; Di Fiore and Pines, 2010; Shindo et al., 2012; Yaakov et al., 2012; Collin et al., 2013; Dick and Gerlich, 2013).

Mentions: Our results, together with those from previous single-cell studies, provide a detailed temporal picture of how yeast cells progress toward the metaphase–anaphase transition (Fig. 7). The process begins with inactivation of the SAC, which inhibits APC/CCdc20 activity until all sister chromatids are properly attached to the spindle. Activated APC/CCdc20 first degrades the S cyclin Clb5 with a mean half-life of 3.4 min. About 6 min later, securin is degraded with a mean half-life of 4.7 min. Soon after securin degradation begins, separase is abruptly activated, and only 1 min is required for separase to cleave enough cohesin to promote sister chromatid separation (Yaakov et al., 2012). By the time of sister chromatid separation, Clb5 is fully degraded but more than half of securin remains.


Multiple mechanisms determine the order of APC/C substrate degradation in mitosis.

Lu D, Hsiao JY, Davey NE, Van Voorhis VA, Foster SA, Tang C, Morgan DO - J. Cell Biol. (2014)

APC/C substrate degradation timing in yeast and mammalian cells. (A) Summary of the regulatory events leading to the metaphase–anaphase transition in yeast and mammalian cells, and the mechanisms that determine the timing and order of APC/CCdc20 substrate degradation in wild-type cells. (B) In yeast, defects in SAC function cause earlier Clb5 destruction but do not affect the timing of securin destruction. In contrast, in mammalian cells, SAC defects result in earlier cyclin A and securin destruction and anaphase onset. (C) In a prolonged SAC arrest, securin is stable, whereas Cks1 and the ABBA motif promote slow degradation of Clb5 and cyclin A. The diagrams in this figure are based on the current work and many previous studies (J. Pines, personal communication; Clute and Pines, 1999; den Elzen and Pines, 2001; Geley et al., 2001; Hagting et al., 2002; Wolthuis et al., 2008; Di Fiore and Pines, 2010; Shindo et al., 2012; Yaakov et al., 2012; Collin et al., 2013; Dick and Gerlich, 2013).
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4195823&req=5

fig7: APC/C substrate degradation timing in yeast and mammalian cells. (A) Summary of the regulatory events leading to the metaphase–anaphase transition in yeast and mammalian cells, and the mechanisms that determine the timing and order of APC/CCdc20 substrate degradation in wild-type cells. (B) In yeast, defects in SAC function cause earlier Clb5 destruction but do not affect the timing of securin destruction. In contrast, in mammalian cells, SAC defects result in earlier cyclin A and securin destruction and anaphase onset. (C) In a prolonged SAC arrest, securin is stable, whereas Cks1 and the ABBA motif promote slow degradation of Clb5 and cyclin A. The diagrams in this figure are based on the current work and many previous studies (J. Pines, personal communication; Clute and Pines, 1999; den Elzen and Pines, 2001; Geley et al., 2001; Hagting et al., 2002; Wolthuis et al., 2008; Di Fiore and Pines, 2010; Shindo et al., 2012; Yaakov et al., 2012; Collin et al., 2013; Dick and Gerlich, 2013).
Mentions: Our results, together with those from previous single-cell studies, provide a detailed temporal picture of how yeast cells progress toward the metaphase–anaphase transition (Fig. 7). The process begins with inactivation of the SAC, which inhibits APC/CCdc20 activity until all sister chromatids are properly attached to the spindle. Activated APC/CCdc20 first degrades the S cyclin Clb5 with a mean half-life of 3.4 min. About 6 min later, securin is degraded with a mean half-life of 4.7 min. Soon after securin degradation begins, separase is abruptly activated, and only 1 min is required for separase to cleave enough cohesin to promote sister chromatid separation (Yaakov et al., 2012). By the time of sister chromatid separation, Clb5 is fully degraded but more than half of securin remains.

Bottom Line: The spindle assembly checkpoint delays the onset of Clb5 degradation but does not influence securin degradation.The degradation of securin and Dbf4 is delayed by Cdk1-dependent phosphorylation near their Cdc20-binding sites.Thus, a remarkably diverse array of mechanisms generates robust ordering of APC/C(Cdc20) substrate destruction.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Physiology and Department of Biochemistry and Biophysics and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158.

Show MeSH
Related in: MedlinePlus