br Conflict of interest br Introduction HAT is

Conflict of interest
Introduction HAT1 is the founding member of an expanding class of enzymes known as type B histone acetyltransferases (HATs). HATs are divided into two categories, type A and type B [1]. The type A HATs are nuclear enzymes that acetylate histones in the context of Thieno-GTP and their role in a variety of nuclear processes is well characterized. Traditionally, type B HATs are distinguished by their specificity for free histone substrates and their partial cytoplasmic localization. Based on these properties, type B HATs are thought to be involved in the acetylation of histones H3 and H4 that occurs rapidly upon their synthesis.
Acetylation of newly synthesized histones In the mid-1970s it was demonstrated that newly synthesized histone H4 is rapidly acetylated in the cytoplasm following its synthesis [2], [3], [4]. Subsequently, histone H3 was also shown to be acetylated rapidly after translation [4]. In the case of histone H4, acetylation of newly synthesized molecules was found to occur in a precise pattern that is highly conserved across eukaryotic evolution. Of the four lysine residues in the NH2-terminal tail that are subject to acetylation (at positions 5, 8, 12 and 16) there are high levels of modification at lysines 5 and 12 and little or no modification on lysines 8 and 16 [5], [6], [7], [8]. For histone H3, while it appears most organisms acetylate newly synthesized molecules, different patterns of acetylation can be found on the five NH2-terminal tail lysine residues that can be acetylated (at positions 9, 14,18, 23 and 27). For example, in flies (Drosophila melanogaster), newly synthesized H3 is acetylated on lysines 14 and 23 while in tetrahymena (Tetrahymena thermophila) lysines 9 and 14 are acetylated [7]. In Saccharomyces cerevisiae, the situation is not clear. Pulse labeling experiments have shown that there are detectable levels of acetylation on newly synthesized histone H3 at all five lysine residues in the NH2-terminal tail [9]. However, acetylation of histone H3 on lysine 9 was shown to have a peak of abundance in S-phase that is dependent on the Asf1 histone chaperone [10]. Whether there are S-phase peaks of acetylation on the other lysines of the H3 NH2-terminal tail has not been determined. With regard to the acetylation of newly synthesized histone H3, it is important to keep in mind that the proportion of new H3 molecules that are modified is small relative to histone H4. This is particularly true in mammalian cells, where this observation has been made using a variety of techniques [4], [5], [7], [11], [12]. Collectively, these studies indicate that roughly two-thirds of the new H3 molecules are unmodified. Whether the modified and unmodified new histone H3 molecules function in distinct ways during the chromatin assembly process has not been determined. The NH2-terminal tail acetylation of the newly synthesized H3 and H4 molecules is a transient modification. Once these histones are transported into the nucleus and assembled into chromatin they are deacetylated during the process of chromatin maturation. During this maturation process, which lasts for 20–60min in mammalian cells, histone H1 becomes associated with chromatin increasing the stability of nucleosomes [13]. In addition to the acetylation that occurs on the NH2-terminal tails, acetylation of lysine residues in the core domain of newly synthesized histones H3 and H4 has recently been observed. The most well-characterized core domain acetylation occurs on lysine 56 of histone H3 [14], [15], [16]. Lysine 56 is located at the end of the α-N helix of histone H3 and is a point of contact with DNA at the entry/exit point of the nucleosome. Thus, H3 lysine 56 acetylation may be capable of physically altering the contact between histone H3 and DNA [17]. Histone H3 lysine 56 acetylation occurs on newly synthesized histones, peaks during S-phase and is removed from histones in G2/M [16], [18], [19]. Mutations in yeast that alter H3 lysine 56 to mimic the constitutively unacetylated state (H3 K56R) result in cells that have increased levels of chromosomal breaks and are sensitive to DNA damaging agents [16], [18], [19], [20], [21], [22], [23], [24], [25], [26]. Evidence suggests that H3 lysine 56 acetylation plays an important role in both replication-coupled and replication-independent chromatin assembly as well as the reassembly of chromatin structure that accompanies DNA damage repair [16], [27], [28], [29], [30]. A critical function of H3 lysine 56 acetylation in these processes may be to regulate interactions with histone chaperones as this modification has been shown to promote the association of H3 with both the CAF-1 and Rtt106 histone chaperones [31]. While originally thought to be limited to yeast, H3 lysine 56 acetylation is also found in higher eukaryotes and may play important roles in stem cell biology and cancer progression [32], [33].