Two factor authentication: Asf1 mediates crosstalk between H3 K14 and K56 acetylation

• Published in: Nucleic acids research 2019-08, Vol.47 (14), p.7380-7391
• Main Authors: Cote, Joy M, Kuo, Yin-Ming, Henry, Ryan A, Scherman, Hataichanok, Krzizike, Daniel D, Andrews, Andrew J
• Format: Article
• Language: English
• Subjects: Acetylation; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Gene regulation, Chromatin and Epigenetics; Histone Acetyltransferases - genetics; Histone Acetyltransferases - metabolism; Histones - metabolism; Lysine - metabolism; Molecular Chaperones - genetics; Molecular Chaperones - metabolism; Mutation; Protein Binding; Protein Processing, Post-Translational; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Substrate Specificity
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/gkz508

Abstract The ability of histone chaperone Anti-silencing factor 1 (Asf1) to direct acetylation of lysine 56 of histone H3 (H3K56ac) represents an important regulatory step in genome replication and DNA repair. In Saccharomyces cerevisiae, Asf1 interacts functionally with a second chaperone, Vps75, and the lysine acetyltransferase (KAT) Rtt109. Both Asf1 and Vps75 can increase the specificity of histone acetylation by Rtt109, but neither alter selectivity. However, changes in acetylation selectivity have been observed in histones extracted from cells, which contain a plethora of post-translational modifications. In the present study, we use a series of singly acetylated histones to test the hypothesis that histone pre-acetylation and histone chaperones function together to drive preferential acetylation of H3K56. We show that pre-acetylated H3K14ac/H4 functions with Asf1 to drive specific acetylation of H3K56 by Rtt109–Vps75. Additionally, we identified an exosite containing an acidic patch in Asf1 and show that mutations to this region alter Asf1-mediated crosstalk that changes Rtt109–Vps75 selectivity. Our proposed mechanism suggests that Gcn5 acetylates H3K14, recruiting remodeler complexes, allowing for the Asf1-H3K14ac/H4 complex to be acetylated at H3K56 by Rtt109–Vps75. This mechanism explains the conflicting biochemical data and the genetic links between Rtt109, Vps75, Gcn5 and Asf1 in the acetylation of H3K56.