A functional analysis reveals dependence on the anaphase-promoting complex for prolonged life span in yeast.
Defects in anaphase-promoting complex (APC) activity, which regulates mitotic progression and chromatin assembly, results in genomic instability, a hallmark of premature aging and cancer. We investigated whether APC-dependent genomic stability affects aging and life span in yeast. Utilizing replicative and chronological aging assays, the APC was shown to promote longevity. Multicopy expression of genes encoding Snf1p (MIG1) and PKA (PDE2) aging-pathway components suppressed apc5CA phenotypes, suggesting their involvement in APC-dependent longevity. While it is known that PKA inhibits APC activity and reduces life span, a link between the Snf1p-inhibited Mig1p transcriptional modulator and the APC is novel. Our mutant analysis supports a model in which Snf1p promotes extended life span by inhibiting the negative influence of Mig1p on the APC. Consistent with this, we found that increased MIG1 expression reduced replicative life span, whereas mig1Delta mutations suppressed the apc5CA chronological aging defect. Furthermore, Mig1p and Mig2p activate APC gene transcription, particularly on glycerol, and mig2Delta, but not mig1Delta, confers a prolonged replicative life span in both APC5 and acp5CA cells. However, glucose repression of APC genes was Mig1p and Mig2p independent, indicating the presence of an uncharacterized factor. Therefore, we propose that APC-dependent genomic stability is linked to prolonged longevity by the antagonistic regulation of the PKA and Snf1p pathways.
Harkness
Troy A A
TA
Department of Anatomy and Cell Biology, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada.
Shea
Kyla A
KA
Legrand
Charmaine
C
Brahmania
Mayur
M
Davies
Gerald F
GF
D000375:Aging / Q000502:physiology*; D064173:Anaphase-Promoting Complex-Cyclosome; D064193:Apc5 Subunit, Anaphase-Promoting Complex-Cyclosome; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; D042822:Genomic Instability; D008136:Longevity; D010641:Phenotype; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D043743:Ubiquitin-Protein Ligase Complexes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
C577378:APC5 protein, S cerevisiae; D064193:Apc5 Subunit, Anaphase-Promoting Complex-Cyclosome; D029701:Saccharomyces cerevisiae Proteins; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; D044767:Ubiquitin-Protein Ligases; C071570:SNF1-related protein kinases; D017346:Protein Serine-Threonine Kinases; D010727:Phosphoric Diester Hydrolases; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2