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| The EMBO Journal
(2000) 19, 3739–3749, doi:10.1093/emboj/19.14.3739 |
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| Cyclophilin A and Ess1 interact with and regulate silencing by the Sin3–Rpd3 histone deacetylase |
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| Miguel Arévalo-Rodríguez1, 2, Maria E. Cardenas1, Xiaoyun Wu3, Steven D. Hanes3 and Joseph Heitman1, 2 |
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1 Departments of Genetics, Pharmacology and Cancer Biology, Microbiology and Medicine, Durham, NC 27710, USA 2 The Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA 3 Molecular Genetics Program, Wadsworth Center, New York State Department of Health and Department of Biomedical Sciences, School of Public Health, State University of New York, Albany, NY 12208, USA To whom correspondence should be addressed Joseph Heitman, heitm001@duke.edu Received 2 November 1999; Revised 30 May 2000; Accepted 30 May 2000. |
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| Abstract |
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| Three families of prolyl isomerases have been identified: cyclophilins, FK506-binding proteins (FKBPs) and parvulins. All 12 cyclophilins and FKBPs are dispensable for growth in yeast, whereas the one parvulin homolog, Ess1, is essential. We report here that cyclophilin A becomes essential when Ess1 function is compromised. We also show that overexpression of cyclophilin A suppresses ess1 conditional and null mutations, and that cyclophilin A enzymatic activity is required for suppression. These results indicate that cyclophilin A and Ess1 function in parallel pathways and act on common targets by a mechanism that requires prolyl isomerization. Using genetic and biochemical approaches, we found that one of these targets is the Sin3–Rpd3 histone deacetylase complex, and that cyclophilin A increases and Ess1 decreases disruption of gene silencing by this complex. We show that conditions that favor acetylation over deacetylation suppress ess1 mutations. Our findings support a model in which Ess1 and cyclophilin A modulate the activity of the Sin3–Rpd3 complex, and excess histone deacetylation causes mitotic arrest in ess1 mutants. |
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| Keywords: cyclosporin A, HDAC, parvulin, Pin1, prolyl isomerases |
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