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Research Paper|Volume 8, Issue 4|pp 810—830

Mitotic degradation of yeast Fkh1 by the Anaphase Promoting Complex is required for normal longevity, genomic stability and stress resistance

Mackenzie E. Malo1, Spike D.L. Postnikoff1, Terra G. Arnason1,2, Troy A.A. Harkness1
  • 1Department of Anatomy and Cell Biology, University of Saskatchewan, Saskatchewan S7N 5E5, Canada
  • 2Department of Medicine, University of Saskatchewan, Saskatchewan S7N 5E5, Canada
Received: March 3, 2016Accepted: April 3, 2016Published: April 19, 2016
https://doi.org/10.18632/aging.100949

Copyright: © 2016 Malo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

The Saccharomyces cerevisiae Forkhead Box (Fox) orthologs, Forkheads (Fkh) 1 and 2, are conserved transcription factors required for stress response, cell cycle progression and longevity. These yeast proteins play a key role in mitotic progression through activation of the ubiquitin E3 ligase Anaphase Promoting Complex (APC) via transcriptional control. Here, we used genetic and molecular analyses to demonstrate that the APC E3 activity is necessary for mitotic Fkh1 protein degradation and subsequent cell cycle progression. We report that Fkh1 protein degradation occurs specifically during mitosis, requires APCCdc20 and proteasome activity, and that a stable Fkh1 mutant reduces normal chronological lifespan, increases genomic instability, and increases sensitivity to stress. Our data supports a model whereby cell cycle progression through mitosis and G1 requires the targeted degradation of Fkh1 by the APC. This is significant to many fields as these results impact our understanding of the mechanisms underpinning the control of aging and cancer.