PMID:15082529

Citation	Pappas, DL Jr, Frisch, R and Weinreich, M (2004) The NAD(+)-dependent Sir2p histone deacetylase is a negative regulator of chromosomal DNA replication. Genes Dev. 18:769-81
Abstract	The establishment of DNA synthesis during the S phase is a multistep process that occurs in several stages beginning in late mitosis. The first step is the formation of a large prereplicative complex (pre-RC) at individual replication origins and occurs during exit from mitosis and entry into G1 phase. To better understand the genetic requirements for pre-RC formation, we selected chromosomal suppressors of a temperature-sensitive cdc6-4 mutant defective for pre-RC assembly. Loss-of-function mutations in the chromatin-modifying genes SIR2, and to a lesser extent in SIR3 and SIR4, suppressed the cdc6-4 temperature-sensitive lethality. This suppression was independent of the well-known silencing roles for the SIR proteins at the HM loci, at telomeres, or at the rDNA locus. A deletion of SIR2 uniquely rescued both the DNA synthesis defect of the cdc6-4 mutant and its severe plasmid instability phenotype for many origins. A SIR2 deletion suppressed additional initiation mutants affecting pre-RC assembly but not mutants that act subsequently. These findings suggest that Sir2p negatively regulates the initiation of DNA replication through a novel mechanism and reveal another connection between proteins that initiate DNA synthesis and those that establish silent heterochromatin in budding yeast.
Links	PubMed PMC387417 Online version:10.1101/gad.1173204
Keywords	Cell Cycle Proteins/genetics; Cell Cycle Proteins/metabolism; Chromosomes, Fungal/genetics; DNA Replication; DNA, Fungal/metabolism; DNA, Ribosomal/genetics; DNA, Ribosomal/metabolism; Gene Deletion; Gene Expression Regulation, Fungal; Gene Silencing; Histone Deacetylases/genetics; Histone Deacetylases/metabolism; MCM1 Protein/genetics; MCM1 Protein/metabolism; Mutation; NAD/metabolism; Phenotype; Plasmids; Saccharomyces cerevisiae/genetics; Saccharomyces cerevisiae Proteins; Silent Information Regulator Proteins, Saccharomyces cerevisiae/genetics; Silent Information Regulator Proteins, Saccharomyces cerevisiae/metabolism; Sirtuin 2; Sirtuins/genetics; Sirtuins/metabolism; Telomere/genetics; Temperature
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