The anaphase promoting complex regulates yeast lifespan and rDNA stability by targeting Fob1 for degradation
Genomic stability, stress response, and nutrient signaling all play critical, evolutionarily conserved roles in lifespan determination. However, the molecular mechanisms coordinating these processes with longevity remain unresolved. Here we investigate the involvement of the yeast anaphase promoting...
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| Veröffentlicht in: | Genetics (Austin) 2014-03, Vol.196 (3), p.693-709 |
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| creator | Menzel, Johannes Malo, Mackenzie E Chan, Cynthia Prusinkiewicz, Martin Arnason, Terra G Harkness, Troy A A |
| description | Genomic stability, stress response, and nutrient signaling all play critical, evolutionarily conserved roles in lifespan determination. However, the molecular mechanisms coordinating these processes with longevity remain unresolved. Here we investigate the involvement of the yeast anaphase promoting complex (APC) in longevity. The APC governs passage through M and G1 via ubiquitin-dependent targeting of substrate proteins and is associated with cancer and premature aging when defective. Our two-hybrid screen utilizing Apc5 as bait recovered the lifespan determinant Fob1 as prey. Fob1 is unstable specifically in G1, cycles throughout the cell cycle in a manner similar to Clb2 (an APC target), and is stabilized in APC (apc5(CA)) and proteasome (rpn10) mutants. Deletion of FOB1 increased replicative lifespan (RLS) in wild type (WT), apc5(CA), and apc10 cells, and suppressed apc5(CA) cell cycle progression and rDNA recombination defects. Alternatively, increased FOB1 expression decreased RLS in WT cells, but did not reduce the already short apc5(CA) RLS, suggesting an epistatic interaction between apc5(CA) and fob1. Mutation to a putative L-Box (Fob1(E420V)), a Destruction Box-like motif, abolished Fob1 modifications, stabilized the protein, and increased rDNA recombination. Our work provides a mechanistic role played by the APC to promote replicative longevity and genomic stability in yeast. |
| doi_str_mv | 10.1534/genetics.113.158949 |
| format | Article |
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However, the molecular mechanisms coordinating these processes with longevity remain unresolved. Here we investigate the involvement of the yeast anaphase promoting complex (APC) in longevity. The APC governs passage through M and G1 via ubiquitin-dependent targeting of substrate proteins and is associated with cancer and premature aging when defective. Our two-hybrid screen utilizing Apc5 as bait recovered the lifespan determinant Fob1 as prey. Fob1 is unstable specifically in G1, cycles throughout the cell cycle in a manner similar to Clb2 (an APC target), and is stabilized in APC (apc5(CA)) and proteasome (rpn10) mutants. Deletion of FOB1 increased replicative lifespan (RLS) in wild type (WT), apc5(CA), and apc10 cells, and suppressed apc5(CA) cell cycle progression and rDNA recombination defects. Alternatively, increased FOB1 expression decreased RLS in WT cells, but did not reduce the already short apc5(CA) RLS, suggesting an epistatic interaction between apc5(CA) and fob1. Mutation to a putative L-Box (Fob1(E420V)), a Destruction Box-like motif, abolished Fob1 modifications, stabilized the protein, and increased rDNA recombination. Our work provides a mechanistic role played by the APC to promote replicative longevity and genomic stability in yeast.</description><identifier>ISSN: 1943-2631</identifier><identifier>ISSN: 0016-6731</identifier><identifier>EISSN: 1943-2631</identifier><identifier>DOI: 10.1534/genetics.113.158949</identifier><identifier>PMID: 24361936</identifier><identifier>CODEN: GENTAE</identifier><language>eng</language><publisher>United States: Genetics Society of America</publisher><subject>Anaphase-Promoting Complex-Cyclosome - genetics ; Anaphase-Promoting Complex-Cyclosome - metabolism ; Binding Sites ; Cell Cycle ; Cellular biology ; DNA, Fungal - metabolism ; DNA, Ribosomal - metabolism ; Fungal Proteins - genetics ; Fungal Proteins - metabolism ; Gene Expression Regulation, Fungal ; Genome, Fungal ; Genomic Instability ; Genomics ; Investigations ; Mutation ; Two-Hybrid System Techniques ; Yeast ; Yeasts - growth & development ; Yeasts - metabolism</subject><ispartof>Genetics (Austin), 2014-03, Vol.196 (3), p.693-709</ispartof><rights>Copyright Genetics Society of America Mar 2014</rights><rights>Copyright © 2014 by the Genetics Society of America 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c532t-500668baa818ae4461221347f0fa81f45f82412884103e4c04432955923f3cd33</citedby><cites>FETCH-LOGICAL-c532t-500668baa818ae4461221347f0fa81f45f82412884103e4c04432955923f3cd33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24361936$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Menzel, Johannes</creatorcontrib><creatorcontrib>Malo, Mackenzie E</creatorcontrib><creatorcontrib>Chan, Cynthia</creatorcontrib><creatorcontrib>Prusinkiewicz, Martin</creatorcontrib><creatorcontrib>Arnason, Terra G</creatorcontrib><creatorcontrib>Harkness, Troy A A</creatorcontrib><title>The anaphase promoting complex regulates yeast lifespan and rDNA stability by targeting Fob1 for degradation</title><title>Genetics (Austin)</title><addtitle>Genetics</addtitle><description>Genomic stability, stress response, and nutrient signaling all play critical, evolutionarily conserved roles in lifespan determination. 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Mutation to a putative L-Box (Fob1(E420V)), a Destruction Box-like motif, abolished Fob1 modifications, stabilized the protein, and increased rDNA recombination. 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However, the molecular mechanisms coordinating these processes with longevity remain unresolved. Here we investigate the involvement of the yeast anaphase promoting complex (APC) in longevity. The APC governs passage through M and G1 via ubiquitin-dependent targeting of substrate proteins and is associated with cancer and premature aging when defective. Our two-hybrid screen utilizing Apc5 as bait recovered the lifespan determinant Fob1 as prey. Fob1 is unstable specifically in G1, cycles throughout the cell cycle in a manner similar to Clb2 (an APC target), and is stabilized in APC (apc5(CA)) and proteasome (rpn10) mutants. Deletion of FOB1 increased replicative lifespan (RLS) in wild type (WT), apc5(CA), and apc10 cells, and suppressed apc5(CA) cell cycle progression and rDNA recombination defects. Alternatively, increased FOB1 expression decreased RLS in WT cells, but did not reduce the already short apc5(CA) RLS, suggesting an epistatic interaction between apc5(CA) and fob1. Mutation to a putative L-Box (Fob1(E420V)), a Destruction Box-like motif, abolished Fob1 modifications, stabilized the protein, and increased rDNA recombination. Our work provides a mechanistic role played by the APC to promote replicative longevity and genomic stability in yeast.</abstract><cop>United States</cop><pub>Genetics Society of America</pub><pmid>24361936</pmid><doi>10.1534/genetics.113.158949</doi><tpages>17</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Oxford University Press Journals All Titles (1996-Current); Alma/SFX Local Collection |
| subjects | Anaphase-Promoting Complex-Cyclosome - genetics Anaphase-Promoting Complex-Cyclosome - metabolism Binding Sites Cell Cycle Cellular biology DNA, Fungal - metabolism DNA, Ribosomal - metabolism Fungal Proteins - genetics Fungal Proteins - metabolism Gene Expression Regulation, Fungal Genome, Fungal Genomic Instability Genomics Investigations Mutation Two-Hybrid System Techniques Yeast Yeasts - growth & development Yeasts - metabolism |
| title | The anaphase promoting complex regulates yeast lifespan and rDNA stability by targeting Fob1 for degradation |
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