@article{ada4b5fe199945e1b6ff3e20d65e59ca,
title = "Modulation of 14-3-3 interaction with phosphorylated histone H3 by combinatorial modification patterns",
abstract = "Post-translational modifications of histones are determining factors in the global and local regulation of genome activity. Phosphorylation of histone H3 is globally associated with mitotic chromatin compaction but occurs in a much more restricted manner during interphase transcriptional regulation of a limited subset of genes. In the course of gene regulation, serine 10 phosphorylation at histone H3 is targeted to a very small fraction of nucleosomes that is highly susceptible to additional acetylation events. Recently, we and others have identified 14-3-3 as a binding protein that recognizes both phosphorylated serine 10 and phosphorylated serine 28 on histone H3. In vitro, the affinity of 14-3-3 for phosphoserine 10 is weak but becomes significantly increased by additional acetylation of either lysine 9 or lysine 14 on the same histone tail. In contrast, the histone H3S28 site matches elements of 14-3-3 high affinity consensus motifs. This region mediates an initial stronger interaction that is less susceptible to modulation by {"}auxiliary{"} modifications. Here we discuss the binding of 14-3-3 proteins to histone H3 in detail and putative biological implications of these interactions.",
keywords = "Epigenetics, Histone code, Methylation, Phosphoacetylation, Transcription",
author = "Stefan Winter and Wolfgang Fischle and Christian Seiser",
note = "Funding Information: Posttranslational modification of histone amino-terminal tails constitutes an important mechanism for the regulation of genome accessibility.54Within the nucleosomal core histones specialized vari- ants have evolved. These take over particular functions in genome organization like centromere maintenance or constitutive hetero- chromatin formation.30,54 Besides the centromere specific isoform, Centromeric protein A (CenpA), three additional histone H3 isoforms are expressed in mammals, designated as H3.1, H3.2 and H3.3. Concerning the transcription-associated interaction between histone H3 and 14-3-3 proteins the latter isoform H3.3 is particular interesting. Histone H3.3 can be incorporated into chromatin outside of S-phase in a replication independent manner (RI), which is important for nucleosome exchange during transcrip- tion.55 Phosphorylation of H3S10 and H3S28 may be spatially separated52,56 and asymmetrically targeted to specific isoforms, as H3.3 was found to be the main species phosphorylated at serine 28 in chicken erythrocytes.57 Because of the spatial separation in interphase cells, H3S10ph and H3S28ph may correlate with transcriptional activation of distinct target genes. As interaction between 14-3-3 and H3S28ph is signifi- cantly stronger,23,25 target genes for H3S28 phosphorylation may be less dependent on additional histone acetylation to enable 14-3-3 binding. For genes targeted by serine 10 phosphorylation, additional lysine acetylation, besides other functions, is important to stabilize the interaction with 14-3-3.25 Although H3S28 phosphorylation may not require additional acetylation for 14-3-3 binding, the modification co-exists with additional histone H3 acetylation in vivo and is even stimulated by preceding HDAC inhibition.52This indicates that histone acetyla- tion may be nevertheless important for transcriptional activation of H3S28ph targets but in a different context than reinforcement of 14-3-3 binding. Based on the in vitro interaction studies the reason Acknowledgements for this may differ between both systems. In the case of H3S10 phos-This work was supported by the Austrian Science Fund (FWF phorylation,bindingof14-3-3isstabilizedbyadditionalacetylation P18746-B12) and the GEN-AU project “Epigenetic Plasticity of the (H3K9orH3K14).TheinteractionwiththeH3S28phosphorylated Mammalian Genome” (Austrian Federal Ministry for Education, histone H3 tail is not modulated (Fig. 2C). However, increased Science and Culture). Stefan Winter is a fellow of the Vienna acetylation suppor{\textcopyright}2008 LANDES BIOSCIENCEts phosphorylation of H3S28and thereby 52 Biocenter PhD program (Austrian Science Fund). creation of an efficiently bound 14-3-3 substrate. Therefore, the References recruitment 14-3-3 to H3S10ph and H3S28ph, may be modulated 1. Darling DL, Yingling J, Wynshaw Boris A. Role of 14-3-3 proteins in eukaryotic signaling by additional acetylation. H3S28 phosphorylation is more abundant Thomas D, Guthridge M, Woodcock J, Lopez A. 14-3-3 protein signaling in development and development. Curr Top Dev Biol 2005; 68:281-315. in the context of hyperacetylated histone H3 and this may directly and growth factor responses. Curr Top Dev Biol 2005; 67:285-303. correlate with increased recruitment of 14-3-3 proteins and tran-Yaffe MB. How do 14-3-3 proteins work?—Gatekeeper phosphorylation and the molecular scriptional activation. Aitken A, Howell S, Jones D, Madrazo J, Martin H, Patel Y, Robinson K. Post-translation-anvil hypothesis. FEBS Lett 2002; 513:53-7. It will be important to determine whether histone H3 acetylation ally modified 14-3-3 isoforms and inhibition of protein kinase C. Mol Cell Biochem 1995; directly mediates increased S28 phosphorylation, or if HDAC inhi-149:41-9. bition modulates the activity of H3S28 kinase activity. lated forms of raf-activating 14-3-3 beta and zeta. In vivo stoichiometric phosphorylation in Aitken A, Howell S, Jones D, Madrazo J, Patel Y. 14-3-3 alpha and delta are the phosphory- brain at a Ser-Pro-Glu-Lys MOTIF. J Biol Chem 1995; 270:5706-9.",
year = "2008",
month = may,
day = "15",
doi = "10.4161/cc.7.10.5946",
language = "English (US)",
volume = "7",
pages = "1336--1342",
journal = "Cell Cycle",
issn = "1538-4101",
publisher = "Taylor and Francis Ltd.",
number = "10",
}