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.
Highlights
The molecular genetics governing eukaryotic longevity are strongly conserved from yeast to mammals [1]
We have described biological roles affected by the Anaphase Promoting Complex (APC) that go beyond lifespan, including critical functions in stress response, mitotic chromatin assembly, and mitoticassociated histone modifications [4, 26,27,28,29]
Since APC5 is an essential gene and a short N-terminal portion of Apc5 does not rescue the apc5CA ts defect [26, 34, 35], we fused the Tandom Affinity Purification (TAP) epitope to the C-terminus of the apc5CA allele and discovered that the ts phenotype is due to an N-terminally truncated protein that likely starts from an internal methionine, and/or undergoes programmed ribosome frameshifting [36] (Fig. S1A)
Summary
The molecular genetics governing eukaryotic longevity are strongly conserved from yeast to mammals [1]. The technique of yeast replicative lifespan (RLS) follows how many mitotic divisions a yeast cell will go through prior to senescence, whereas chronological lifespan (CLS) measures how long a postmitotic population of cells will remain metabolically active [2, 3]. These are two very different measures of the yeast life cycle, and are dictated by similar, yet distinct, sets of genes [3]. The Anaphase Promoting Complex (APC) and the yeast Forkhead (Fkh) proteins (Fkh and Fkh2) interact to play important roles in both lifespan and stress response [4,5,6]
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