The Amazing Acrobat: Yeast's Histone H3K56 Juggles Several Important Roles While Maintaining Perfect Balance

Abstract

Acetylation on lysine 56 of histone H3 of the yeast Saccharomyces cerevisiae has been implicated in many cellular processes that affect genome stability. Despite being the object of much research, the complete scope of the roles played by K56 acetylation is not fully understood even today. The acetylation is put in place at the S-phase of the cell cycle, in order to flag newly synthesized histones that are incorporated during DNA replication. The signal is removed by two redundant deacetylases, Hst3 and Hst4, at the entry to G2/M phase. Its crucial location, at the entry and exit points of the DNA into and out of the nucleosome, makes this a central modification, and dictates that if acetylation and deacetylation are not well concerted and executed in a timely fashion, severe genomic instability arises. In this review, we explore the wealth of information available on the many roles played by H3K56 acetylation and the deacetylases Hst3 and Hst4 in DNA replication and repair.

Keywords: DNA repair; DNA replication; Hst3; Hst4; acetylation/deacetylation; chromatin; genome stability.

Figure 1

Nucleosome assembly with H3 K56-acetylated histones: (A) The newly synthesized H3-H4 dimer is bound by Asf1, which presents it to Rtt109. Rtt109, together with Vps75, acetylates H3 at lysine 56. The H3K56Ac-H4 dimer’s affinity to Rtt101 increases, leading Rtt101-Mms1-Mms22 to ubiquitylate H3 at K121, K122, and K125 of H3, and driving the dissociation of H3K56Ac-H4 from Asf1 and its handoff to the chromatin remodelers CAF-1, Rtt106 and FACT. (B) Following the incorporation of a tetramer containing two H3K56Ac-H4 dimers, two Nap1 proteins bring H2A-H2B dimers to form an octamer. Following the formation of the octamer Hst3 then deacetylates the nucleosome at position K56 of H3.

Figure 2

A summary of the different roles of H3K56Ac: H3K56Ac has been implicated in a variety of processes, related both to replication and to genome stability. Of these processes, evidence exists that ties H3K56Ac to homologous recombination repair pathways, in particular strand invasion and break induced repair (BIR). In addition, there is an effect on mismatch repair, expansions and contractions in the number of trinucleotide repeats, maintenance of origin-less chromosomal segments, and the prevention of chromosomal abnormalities such as mutations and rearrangements. H3K56Ac is also connected to replication, and to firing of origins and cell cycle progression. See text for more details.