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Modulation of Gene Silencing by Cdc7p via H4 K16 Acetylation and Phosphorylation of Chromatin Assembly Factor CAF-1 in .

Young TJ, Cui Y, Irudayaraj J, Kirchmaier AL

CAF-1 is an evolutionarily conserved H3/H4 histone chaperone that plays a key role in replication-coupled chromatin assembly and is targeted to the replication fork via interactions with PCNA, which, if disrupted, leads to epigenetic defects. In , when the silent mating-type locus contains point mutations within the silencer, Sir protein association and silencing is lost. However, mutation of , encoding an S-phase-specific kinase, or subunits of the H4 K16-specific acetyltransferase complex SAS-I, restore silencing to this crippled , Here, we observed that loss of Cac1p, the largest subunit of CAF-1, also restores silencing at , and silencing in both Δ and mutants is suppressed by overexpression of We demonstrate Cdc7p and Cac1p interact in S phase, but not in G1, consistent with observed cell cycle-dependent phosphorylation of Cac1p, and hypoacetylation of chromatin at H4 K16 in both and Δ mutants. Moreover, silencing at ** is restored in cells expressing cac1p mutants lacking Cdc7p phosphorylation sites. We also discovered that Δ and synthetically interact negatively in the presence of DNA damage, but that Cdc7p phosphorylation sites on Cac1p are not required for responses to DNA damage. Combined, our results support a model in which Cdc7p regulates replication-coupled histone modification via a -dependent mechanism involving H4 K16ac deposition, and thereby silencing, while CAF-1-dependent replication- and repair-coupled chromatin assembly are functional in the absence of phosphorylation of Cdc7p consensus sites on CAF-1.


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April, 2019


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