The Histone Deacetylases Sir2 and Rpd3 Act on Ribosomal DNA to Control the Replication Program in Budding Yeast

• Published in: Molecular cell 2014-05, Vol.54 (4), p.691-697
• Main Authors: Yoshida, Kazumasa, Bacal, Julien, Desmarais, Damien, Padioleau, Ismaël, Tsaponina, Olga, Chabes, Andrei, Pantesco, Véronique, Dubois, Emeric, Parrinello, Hugues, Skrzypczak, Magdalena, Ginalski, Krzysztof, Lengronne, Armelle, Pasero, Philippe
• Format: Article
• Language: English
• Subjects: Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Checkpoint Kinase 2 - genetics; Checkpoint Kinase 2 - metabolism; DNA Replication; DNA, Fungal - genetics; DNA, Fungal - metabolism; DNA, Ribosomal - genetics; DNA, Ribosomal - metabolism; Epigenesis, Genetic; Gene Deletion; Genetics; Histone Deacetylases - metabolism; Life Sciences; Mutation; Oligonucleotide Array Sequence Analysis; Replication Origin; Saccharomyces cerevisiae; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Silent Information Regulator Proteins, Saccharomyces cerevisiae - metabolism; Sirtuin 2 - metabolism
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/j.molcel.2014.04.032

In S. cerevisiae, replication timing is controlled by epigenetic mechanisms restricting the accessibility of origins to limiting initiation factors. About 30% of these origins are located within repetitive DNA sequences such as the ribosomal DNA (rDNA) array, but their regulation is poorly understood. Here, we have investigated how histone deacetylases (HDACs) control the replication program in budding yeast. This analysis revealed that two HDACs, Rpd3 and Sir2, control replication timing in an opposite manner. Whereas Rpd3 delays initiation at late origins, Sir2 is required for the timely activation of early origins. Moreover, Sir2 represses initiation at rDNA origins, whereas Rpd3 counteracts this effect. Remarkably, deletion of SIR2 restored normal replication in rpd3Δ cells by reactivating rDNA origins. Together, these data indicate that HDACs control the replication timing program in budding yeast by modulating the ability of repeated origins to compete with single-copy origins for limiting initiation factors. [Display omitted] •Two HDACs, Rpd3 and Sir2, modulate the replication timing program•Rpd3 and Sir2 regulate the activity of rDNA origins in an opposite manner•rDNA and single-copy origins compete for limiting initiation factors•HDACs act on rDNA origins to modulate the replication timing program Yoshida et al. show that Sir2 and Rpd3 control replication timing in budding yeast by regulating the efficiency of ∼200 origins at the rDNA and the formation of extrachromosomal rDNA circles. These repeated origins compete with single-copy origins for limiting initiation factors and are therefore key regulators of the replication program.