Understanding histone acetyltransferase Rtt109 structure and function: how many chaperones does it take?

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Rtt109 (Regulator of Ty1 Transposition 109) is a fungal-specific histone acetyltransferase required for modification of histone H3 K9, K27 and K56. These acetylations are associated with nascent histone H3 and play an integral role in replication-coupled and repair-coupled nucleosome assembly. Rtt109 is unique among acetyltransferases as it is activated by a histone chaperone; either Vps75 (Vacuolar Protein Sorting 75) or Asf1 (Anti-silencing Function 1). Recent biochemical, structural and genetic studies have shed light on the intricacies of this activation. It is now clear that Rtt109-Asf1 acetylates K56, while Rtt109-Vps75 acetylates K9 and K27. This reinforces that Asf1 and Vps75 activate Rtt109 via distinct molecular mechanisms. Structures of Rtt109-Vps75 further imply that Vps75 positions histone H3 in the Rtt109 active site. These structures however raise questions regarding the stoichiometry of the Rtt109-Vps75 complex. This has ramifications for determining the physiological Rtt109 substrate.

Highlights

Histone chaperones Vps75 and Asf1 stimulate Rtt109 acetyltransferase toward histone H3 approximately 100-fold. ► Rtt109-Asf1 acetylates H3 K56, while Rtt109-Vps75 acetylates H3 K9 and K27. ► Auto-acetylation of Rtt109 at K290 is essential and is not influenced by Vps75. ► Based on structural work, the stoichiometry of Vps75-Rtt109 is uncertain; it may be 2:1 or 2:2. ► Vps75 imports Rtt109 into the nucleus, stabilizes Rtt109, and positions H3 for acetylation by Rtt109.

Introduction

Histone acetylation is a crucial regulatory mechanism of DNA-dependent processes such as transcription, replication and repair. It involves histone acetyl-transferase enzymes (HATs) that transfer an acetyl moiety from acetyl-CoA to the ɛ-amine group of a histone lysine residue. The cell contains several HATs, for example Gcn5 (General control nonderepressible 5) (KAT2) (lysine acetyl-transferase), p300/CBP (CREB-binding protein) (KAT3A/B) and Tip60 (Tat interactive protein 60) (KAT5), which between them acetylate different residues on the four core histone proteins [1, 2]. A recurrent feature of HATs is their presence in protein complexes with constituents that regulate their activity and substrate selectivity. Regulation prevents uncontrolled histone acetylation causing aberrant DNA metabolic events. The molecular underpinning of such regulation is challenging to decipher as it requires genetic, biochemical and structural approaches. This review will focus on recent developments relating to the HAT, Rtt109 (Regulator of Ty1 Transposition 109) (KAT11), particularly the molecular details of its interaction with and regulation by histone chaperone, Vps75 (Vacuolar Protein Sorting 75).

Section snippets

Rtt109 substrates

Rtt109 is a fungal-specific HAT historically associated with acetylation of histone H3 K56 (H3 K56Ac) [3, 4, 5]. Recent data, however, also establish H3 K9 and K27 as bona fide Rtt109 targets in yeast [6, 7]. Rtt109-dependent K9Ac and K27Ac eluded detection as unlike K56, these residues are also acetylated by Gcn5 [8]. Residues K9 and K27 are in the H3 disordered tail, while residue K56 is in the H3 histone-fold domain (Figure 1a) [9]. As such, Rtt109 cannot acetylate K56 on H3 that is a

Rtt109 activation – Vps75 versus Asf1

A well-established and intriguing feature of Rtt109 is its stimulation by binding partners Vps75 and Asf1 (Anti-silencing Function 1) [4, 10]. Vps75 and Asf1 are structurally unrelated histone chaperones that interact with histone (H3-H4)2 tetramer and H3-H4 dimer, respectively [15, 16]. The interactions between Vps75/Asf1 and H3-H4 have nanomolar affinity, ten times stronger than that between Rtt109 and H3-H4 [17, 18]. However, both Vps75 and Asf1 enhance the catalytic activity of Rtt109,

Rtt109 catalytic mechanism

Determining how histone chaperones activate Rtt109 ultimately requires insight into Rtt109 catalytic mechanism. Such insight has been gleaned from biochemical analyses [20•, 21•, 23] performed in the wake of the three Rtt109 crystal structures (Figure 1b) [19, 24, 25]. The structures of Rtt109 revealed an overall fold similar to the p300/CBP HAT domain, albeit with a non-conserved active site [19, 24, 26]. The structures also uncovered an acetylated lysine residue (K290) in the vicinity of the

Rtt109-Vps75 structures

Insight into Rtt109 has also emerged from recent crystallographic analysis with Vps75 [20•, 22••, 27•]. Three independent groups have reported a total of five Rtt109-Vps75 structures, with only two of the structures being from the same crystal form (Table 1). Notably, the data obtained by Kolonko et al. are of poor resolution, limiting structural detail and preventing refinement [20]. Collectively the remaining structures reveal three potential interfaces between Rtt109 and Vps75 (interface I,

Future directions

Regardless of the outstanding issues relating to the Rtt109-Vps75 structures, they imply that Vps75 stimulates Rtt109 activity through positioning the histone H3 substrate. As such, there is a clear demand for a more molecular view of Vps75-histone complexes. Initial work with Vps75 homolog Set, clearly paves the way [29]. It will be interesting to see if Vps75 physically blocks K56. It will also be intriguing to determine why Vps75 paralog Nap1 (Nucleosome assembly protein 1) can bind to but

References and recommended reading

Papers of particular interest published within the period of review have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

S.D. and K.L. are supported by the Howard Hughes Medical Institute. K.L. is also supported by the NIH (GM067777 and GM088409). We thank members of the Luger laboratory for helpful discussion.

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