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.
Highlights
Lysine 56 (H3-K56) occupies a strategic location at the ends of the two histone H3’s a-N helices within the nucleosome particle and likely plays a pivotal role in nucleosomal DNA dynamics by making a water mediated hydrogen bond with the DNA that enters and exits the nucleosome [1,2]
In order to explore whether H3-S57 interplays with H3-K56 acetylation we employed a Saccharomyces cerevisiae yeast strain where both endogenous H3 genes were deleted
While H3-S57E was sensitive to both HU and methylmethane sulfonate (MMS), S57A was not sensitive to HU, even at a higher concentration (Figure 3B). These results suggest that histone H3 serine 57 has some role when yeast cells face S-phase stress induced by MMS [34]
Summary
Lysine 56 (H3-K56) occupies a strategic location at the ends of the two histone H3’s a-N helices within the nucleosome particle and likely plays a pivotal role in nucleosomal DNA dynamics by making a water mediated hydrogen bond with the DNA that enters and exits the nucleosome [1,2]. A previously unknown yeast histone acetyl transferase (HAT), Rtt109p, bearing structural resemblance to the mammalian p300/CBP HATs [9,10] has been demonstrated to be responsible for H3-K56 acetylation [11,12]. In mammalian cells, both CBP and GCN5 have been put forward as H3-K56 HATs [13,14]. How H3-K56 facilitates recovery from double strand DNA breaks is still unknown [24,25] it is known that K56 acetylation increases the affinity of histone H3 for the histone chaperones Rtt106p and CAF-1 [26] as well as increasing the ‘breathing’ of DNA entering and exiting the nucleosome 7-fold [27]. 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
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