Histone H3 Serine 57 and Lysine 56 Interplay in Transcription Elongation and Recovery from S-Phase Stress

Abstract

BackgroundAcetylation of lysine 56 of histone H3 plays an important role in the DNA damage response and it has been postulated to play an as yet undefined role in transcription, both in yeast and in higher eukaryotes. Because phosphorylated human histone H3 serine 57 peptides have been detected by mass spectrometry we examined whether H3-S57 phosphorylation interplays with H3-K56 acetylation in vivo.Methodology/Principal FindingsTo explore the physiological role of H3-S57, H3-K56 was mutated to mimic constitutively (un)acetylated forms of H3-K56 and these were combined with constitutively (un)phosphorylated mimics of H3-S57, in yeast. A phosphorylated serine mimic at position 57 lessened sensitivities to a DNA replication fork inhibitor and to a transcription elongation inhibitor that were caused by an acetylated lysine mimic at position 56, while the same substitution exacerbated sensitivities due to mimicking a constitutive non-acetylated lysine at position 56. Strikingly, opposite results were obtained in the context of a serine to alanine substitution at position 57 of histone H3.Conclusions/SignificanceThe phenotypes elicited and the context-dependent interplay of the H3-K56 and -S57 point mutations that mimic their respective modification states suggest that serine 57 phosphorylation promotes a nucleosomal transaction when lysine 56 is acetylated. We speculate that histone H3-S57 couples H3-K56 acetylation to histone quaternary structures involving arginine 40 on histone H4 helix 1.

Histone Chaperones Nap1 and Vps75 Regulate Histone Acetylation during Transcription Elongation

“…The vps75::NatMX and nap1::NatMX strains were generated from Y2454 (MAT␣ ura3⌬0 leu2⌬0 his3⌬1 lys2⌬0 MFA1pr-HIS3 can1⌬0) and mated with the strains noted above to produce the following haploid strains (37) and K9 mutants were expressed from plasmids in a strain where both HHT1 and HHT2 had been deleted, kindly provided by C. Logie, Radboud University, Netherlands. CTK1 was deleted in this strain by integration of the NatMX cassette into the gene (38). Ctk1-WT (where WT is wild type) and Ctk1-D324N and Ctk1-T338A mutants were expressed from plasmids in the ctk1⌬ strain background and were kindly provided by M. J. Solomon Lab, Yale University (39).…”

“…We investigated whether acetylation of H3 K56 was important for transcription elongation. We expressed WT or mutant H3 from a plasmid in a strain where both genomic copies of H3 were deleted (38). In addition, CTK1 was deleted in this strain.…”

DYRK1A phoshorylates histone H3 to differentially regulate the binding of HP1 isoforms and antagonize HP1‐mediated transcriptional repression

“…Decreased acetylation was more specifically detected at H3K14 and H3K56 (Fig 4G,H). Acetylation at this latter position is associated with transcriptional activation in both yeast [23][24][25] and mammalian cells [26][27][28] and possibly linked to H3S57 phosphorylation during transcriptional elongation [29].…”

Epigenomics and the concept of degeneracy in biological systems

“…However, an environmental shift can easily enforce a new round of programming leading to a different more suitable phenotypic outcome [31–38]. In addition to plants and animals, a similar interplay of environmental and epigenetic contexts has also been reported in more elementary pathways, such as the cell autonomous DNA damage response in yeast [39]. …”