Histone H3 Lysine 56 Acetylation: A New Twist in the Chromosome Cycle

Abstract

Several recent reports have identified lysine 56 (K56) as a novel site of acetylation in yeast histone H3. K56 acetylation is predicted to disrupt some of the histone-DNA interactions at the entry and exit points of the nucleosome core particle. This modification occurs in virtually all the newly synthesised histones that are deposited into chromatin during S-phase. Cells with mutations that block K56 acetylation show increased genome instability and hypersensitivity to genotoxic agents that interfere with replication. Removal of K56 acetylation takes place in the G 2 /M phase of the cell cycle and is dependent upon Hst3 and Hst4, two proteins that are related to the NAD + -dependent histone deacetylase Sir2. In response to DNA damage checkpoint activation during S-phase, expression of Hst3/Hst4 is delayed to extend the window of opportunity in which K56 acetylation can act in the DNA damage response. The high abundance of histone H3 K56 acetylation, its regulation and strategic location in the nucleosome core particle raise a number of fascinating issues that we discuss here.

Regulation of Histone H3 Lysine 56 Acetylation in Schizosaccharomyces pombe

“…This modification is mediated by histone acetyltransferases (HATs) 7 and is reversible as the acetyl group can be removed through the action of histone deacetylases (HDACs). Lysine acetylation on histones is best characterized for its role in transcriptional regulation, but evidence for a crucial function during replication and DNA damage tolerance is accumulating (1)(2)(3). Indeed, newly synthesized histones that are deposited throughout the genome during replication are transiently acetylated at several lysine residues (4,5).…”

Cul8/Rtt101 Forms a Variety of Protein Complexes That Regulate DNA Damage Response and Transcriptional Silencing

“…Acetylation of Lys 56 of histone H3 is important for damage tolerance (8), and a recent study has shown that Cul8, Mms1, and Mms22 act downstream of the Lys 56 acetylation pathway (7). Deletion of CUL8, MMS1, MMS22, or ESC4 sen-* This work was supported in part by grants from the Ministry of Education, sitizes the cells to DNA-damaging agents (9 -12).…”

An old HAT in human p300/CBP and yeast Rtt109

“…3 One of these special events is the acetylation of histone H3 Lys56 (H3K56) in yeast that has been critically linked to the regulation of genome stability, cell cycle progression and DNA damage responses. 4 H3K56 is strategically placed on the last turn of a core helix-near the convergent entry and exit points of the wrapped DNA, where its acetylation promotes chromatin unfolding. 3,4 The responsible H3K56 HAT in S. cerevisiae [5][6][7][8][9] and S. pombe 10,11 is Rtt109, a novel AcCoA-dependent enzyme that recruits histone chaperones Asf1 or Vps75 for robust H3K56 acetylation.…”

“…4 H3K56 is strategically placed on the last turn of a core helix-near the convergent entry and exit points of the wrapped DNA, where its acetylation promotes chromatin unfolding. 3,4 The responsible H3K56 HAT in S. cerevisiae [5][6][7][8][9] and S. pombe 10,11 is Rtt109, a novel AcCoA-dependent enzyme that recruits histone chaperones Asf1 or Vps75 for robust H3K56 acetylation. 6,9,11,12 The family relationships of Rtt109 can best be captured by sensitive profile-profile comparison methods such as HHPred 13 that show a distant but significant match to PFAM domain DUF906 (Interpro entry IPR009255) which encompasses the centrally-located HAT domain of p300/CBP orthologs (Fig.…”

“…1), Liu et al, chart the course of a prospective peptide ligand on the surface of p300 and locate an acidic P2 pocket near the P1 site that could sequester conserved Arg or Lys residues posted three to four residues before or after the modified Lys in diverse p300/CBP target proteins. 1 Rtt109 has an exclusive H3K56 substrate [4][5][6][7][8][9][10][11][12] embedded in an RRFQK 56 STE 59 LL sequence that places the target Lys56 on a molecular elbow at the end of a helix 3,4 (underlined residues). The Rtt109 equivalents of the p300 P2 pocket residues are Thr49, Lys 97, Pro286, Lys353 and Lys356, conferring a distinctly more basic character to the pocket (Suppl.…”