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Dependence of ORC Silencing Function on NatA-Mediated N Acetylation in Saccharomyces cerevisiae

Otto-Warburg-Laboratorium, Max-Planck-Institut für Molekulare Genetik,¹ Institut für Chemie/Biochemie, Freie Universität Berlin, Berlin, Germany²

Received 20 July 2004/ Returned for modification 24 August 2004/ Accepted 28 September 2004

N acetylation is one of the most abundant protein modifications in eukaryotes and is catalyzed by N-terminal acetyltransferases (NATs). NatA, the major NAT in Saccharomyces cerevisiae, consists of the subunits Nat1p, Ard1p, and Nat5p and is necessary for the assembly of repressive chromatin structures. Here, we found that Orc1p, the large subunit of the origin recognition complex (ORC), required NatA acetylation for its role in telomeric silencing. NatA functioned genetically through the ORC binding site of the HMR-E silencer. Furthermore, tethering Orc1p directly to the silencer circumvented the requirement for NatA in silencing. Orc1p was N acetylated in vivo by NatA. Mutations that abrogated its ability to be acetylated caused strong telomeric derepression. Thus, N acetylation of Orc1p represents a protein modification that modulates chromatin function in S. cerevisiae. Genetic evidence further supported a functional link between NatA and ORC: (i) nat1 was synthetically lethal with orc2-1 and (ii) the synthetic lethality between nat1 and SUM1-1 required the Orc1 N terminus. We also found Sir3p to be acetylated by NatA. In summary, we propose a model by which N acetylation is required for the binding of silencing factors to the N terminus of Orc1p and Sir3p to recruit heterochromatic factors and establish repression.

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