Academic journal article Genetics

Modulation of Gene Silencing by Cdc7p Via H4 K16 Acetylation and Phosphorylation of Chromatin Assembly Factor CAF-1 in Saccharomyces Cerevisiae

Academic journal article Genetics

Modulation of Gene Silencing by Cdc7p Via H4 K16 Acetylation and Phosphorylation of Chromatin Assembly Factor CAF-1 in Saccharomyces Cerevisiae

Article excerpt

DURING DNA replication, nucleosomes must be disassembled from in front of the replication fork and reassembled behind the replication fork. When the fork travels through loci, reassembly must be coordinated to ensure that locus-specific patterns of histone modifications on nucleosomes and specialized chromatin are maintained on nucleosomes containing parental histones, as well as recreated on nucleosomes containing newly synthesized histones. This reconstruction is essential to ensure that epigenetic states are inherited (Burgess and Zhang 2010; Margueron and Reinberg 2010; Alabert and Groth 2012). Nucleosome assembly associated with DNA replication is thought to primarily involve deposition of a histone (H3/H4)2 tetramer, which is then followed by the addition of H2A/H2B dimers (Smith and Stillman 1991; Ransom et al. 2010; Xu et al. 2010; Mattiroli et al. 2017). Asf1p, CAF-1, and Rtt106p are histone chaperones that play predominant roles in transporting histones H3/H4 and chromatin assembly during DNA replication in Saccharomyces cerevisiae, although yeast lacking these assembly factors singly or in combination remain viable. The interaction between H3/H4 and Rtt106p or CAF-1 is promoted by H3 K56ac (Li et al. 2008), which requires Asf1p to present H3/H4 as a substrate for the sole H3 K56-specific acetyltransferase Rtt109p (Driscoll et al. 2007; Han et al. 2007; Tsubota et al. 2007). This effect, in combination with the ability of CAF-1 and Rtt106p to bind H3/H4 tetramers (Liu et al. 2010; Fazly et al. 2012; Mattiroli et al. 2017), and Asf1p to bind exclusively to H3/H4 dimers in a manner that prevents H3/H4 tetramer formation (English et al. 2006; Natsume et al 2007), supports a model in which Asfip functions upstream of CAF-1 and Rtt106p during replication-coupled chromatin assembly, and transfers H3/H4 to CAF-1 or Rtt106p. In this model, CAF-1 or Rtt106p then promotes H3/H4 tetramer formation onto newly synthesized DNA, with CAF-1 likely being recruited to the replication fork through an interaction with the DNA processivity factor PCNA (Shibahara and Stillman 1999; Winkler et al. 2012). As Rtt106p can also bind Cac1p independent of H3/H4 in vitro as well as co-immunoprecipitate Cac2p in a CAC1dependent manner in vivo (Huang et al. 2005), both chaperones potentially function together, or directly exchange H3/ H4 during chromatin assembly.

The fidelity of replication-coupled chromatin assembly impacts gene silencing in S. cerevisiae, as well as epigenetic processes in organisms ranging from Schizosaccharomyces pombe to Drosophila to humans [see Dohke et al. (2008), Huang et al. (2010), Alabert and Groth (2012), and Young and Kirchmaier (2013), and references within]. In budding yeast, silent chromatin is transcriptionally inactive and is found in telomeric regions, the rDNA locus, and the silent mating-type loci. Silent chromatin is formed at the silent mating-type loci HMR and HML by the initial recruitment of Silent Information Regulator proteins Sir1p, Sir2p, Sir3p, and Sir4p to regulatory silencer regions, E and I, ofthese HM loci. Upon being recruited to the HMR-E silencer, Sir2p, Sir3p, and Sir4p then propagate throughout the region to form silent chromatin (Hoppe et al. 2002; Rusché et al. 2002; Bose et al. 2004). Sir propagation requires the deacetylation of H4 K16 by activity of the NAD+-dependent histone deacetylase Sir2p, which generates a higher-affinity binding site for Sir3p (Hecht et al. 1995; Braunstein et al. 1996; Carmen et al. 2002; Hoppe et al. 2002; Rusché et al. 2002; Buchberger et al. 2008). Once established, silent chromatin is efficiently maintained throughout the cell cycle and inherited upon DNA replication, thereby ensuring a transcriptionally silenced epigenetic state in cells and their progeny [see Pillus and Rine (1989), Gottschling et al. (1990), and Young and Kirchmaier (2013), and references within].

Screens designed to uncover mutations that restore silencing at a HMR locus containing a crippled E silencer, e··, have identified several factors involved in DNA replication or chromatin modification (Axelrod and Rine 1991; EhrenhoferMurray et al. …

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