Analysis of Phosphorylation-Dependent Protein–Protein Interactions of Histone H3

Klingberg, Rebecca; Jost, Jan Oliver; Schümann, Michael; Gelato, Kathy A.; Fischle, Wolfgang; Krause, Eberhard; Schwarzer, Dirk

doi:10.1021/cb500563n

Cited by 21 publications

(24 citation statements)

References 51 publications

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“…Histone acetyltransferases, including HAT1, acetylate histone N-terminal tails relaxing histone-DNA interactions, remodeling the nucleosome to a euchromatic state. RBBP7 is a coactivator of HAT1 (17). Our bioinformatics analysis also revealed an AMPK phosphorylation sequence in HAT1 (Fig.…”

Section: Resultsmentioning

confidence: 99%

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AMPK promotes mitochondrial biogenesis and function by phosphorylating the epigenetic factors DNMT1, RBBP7, and HAT1

et al. 2017

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Adenosine monophosphate (AMP)–activated protein kinase (AMPK) acts as a master regulator of cellular energy homeostasis by directly phosphorylating metabolic enzymes and nutrient transporters and by indirectly promoting the transactivation of nuclear genes involved in mitochondrial biogenesis and function. We explored the mechanism of AMPK-mediated induction of gene expression. We identified AMPK consensus phosphorylation sequences in three proteins involved in nucleosome remodeling: DNA methyltransferase 1 (DNMT1), retinoblastoma binding protein 7 (RBBP7), and histone acetyltransferase 1 (HAT1). DNMT1 mediates DNA methylation that limits transcription factor access to promoters and is inhibited by RBBP7. Acetylation of histones by HAT1 creates a more relaxed chromatin-DNA structure that favors transcription. AMPK-mediated phosphorylation resulted in the activation of HAT1 and inhibition of DNMT1. For DNMT1, this inhibition was both a direct effect of phosphorylation and the result of increased interaction with RBBP7. In human umbilical vein cells, pharmacological AMPK activation or pulsatile shear stress triggered nucleosome remodeling and decreased cytosine methylation, leading to increased expression of nuclear genes encoding factors involved in mitochondrial biogenesis and function, such as peroxisome proliferator–activated receptor gamma coactivator–1α (PGC-1α), transcription factor A (Tfam), and uncoupling proteins 2 and 3 (UCP2 and UCP3). Similar effects were seen in the aortas of mice given pharmacological AMPK activators, and these effects required AMPK2α. These results enhance our understanding of AMPK-mediated mitochondrial gene expression through nucleosome remodeling.

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Section: Resultsmentioning

confidence: 99%

“…Because HAT1 and RBBP7 form an active acetyltransferase complex to acetylate histone 4 (H4) (acetyl-H4K5), which increases euchromatin (the decondensed chromatin state) (17, 19), we examined the effect of AMPK activation on HAT1 activity. AICAR or metformin increased HAT1 activity in AMPK +/+ MEFs but not in AMPK −/− MEFs (Fig.…”

Section: Resultsmentioning

confidence: 99%

AMPK promotes mitochondrial biogenesis and function by phosphorylating the epigenetic factors DNMT1, RBBP7, and HAT1

et al. 2017

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“…1). (2) modulates epigenetic information coming from K9 methylation by regulating K9 methyltransferases [10,56,[67][68][69] and demethylases [74,75]; (3) as K9 can be both methylated and acetylated, H3S10ph also affects K9ac, it acts in synergy with this histone mark and increases efficiency of acetylation reactions [57,105]; (4) same effects as for K9ac can be seen for K14ac [7]. H3S10ph can also affect histone post-translational modifications in trans, like histone H4 acetylation, attracting H4 acetyltransferases and protecting from deacetylase action [62,65] displaced nontemplate single-stranded DNA, called R-loops [43,44].…”

Section: H3s10 Phosphorylation In Chromatin Dynamics and Cell Cycle Rmentioning

confidence: 99%

“…In vitro pull-down assays with N-terminal tail of histone H3 phosphorylated at S10 followed by mass spectrometry identified 6 members of 14-3-3 protein family as H3S10ph binding partners [57,58]. 14-3-3s form a well-conserved, abundant family of phosphoacetyl-binding proteins that can interact with over 300 partners including many transcriptional regulators and chromatin-modifying proteins (reviewed in [59]).…”

Section: H3s10 Phosphorylation In the Regulation Of Transcription In mentioning

confidence: 99%

Rebelled epigenome: histone H3S10 phosphorylation and H3S10 kinases in cancer biology and therapy

Komar

Juszczyński

2020

Clin Epigenet

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Background With the discovery that more than half of human cancers harbor mutations in chromatin proteins, deregulation of epigenetic mechanisms has been recognized a hallmark of malignant transformation. Post-translational modifications (PTMs) of histone proteins, as main components of epigenetic regulatory machinery, are also broadly accepted as therapeutic target. Current “epigenetic” therapies target predominantly writers, erasers and readers of histone acetylation and (to a lesser extent) methylation, leaving other types of PTMs largely unexplored. One of them is the phosphorylation of serine 10 on histone H3 (H3S10ph). Main body H3S10ph is emerging as an important player in the initiation and propagation of cancer, as it facilitates cellular malignant transformation and participates in fundamental cellular functions. In normal cells this histone mark dictates the hierarchy of additional histone modifications involved in the formation of protein binding scaffolds, transcriptional regulation, blocking repressive epigenetic information and shielding gene regions from heterochromatin spreading. During cell division, this mark is essential for chromosome condensation and segregation. It is also involved in the function of specific DNA–RNA hybrids, called R-loops, which modulate transcription and facilitate chromosomal instability. Increase in H3S10ph is observed in numerous cancer types and its abundance has been associated with inferior prognosis. Many H3S10-kinases, including MSK1/2, PIM1, CDK8 and AURORA kinases, have been long considered targets in cancer therapy. However, since these proteins also participate in other critical processes, including signal transduction, apoptotic signaling, metabolic fitness and transcription, their chromatin functions are often neglected. Conclusions H3S10ph and enzymes responsible for deposition of this histone modification are important for chromatin activity and oncogenesis. Epigenetic-drugs targeting this axis of modifications, potentially in combination with conventional or targeted therapy, provide a promising angle in search for knowledge-driven therapeutic strategies in oncology.

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“…Phosphorylation of H3S10 has been investigated with peptide probes containing a phosphonate mimic of phosphorylated serine. 127 This probe cannot be dephosphorylated by phosphatases and bound 14-3-3 proteins from cellular lysates. It was also used to study repressive effects of H3S10ph on chromatin-factor recruitment.…”

Section: Binding Proteins Of Phosphorylated Histonesmentioning

confidence: 99%

Probing Chromatin-modifying Enzymes with Chemical Tools

Fischle

Schwarzer

2016

ACS Chem. Biol.

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2 Glossary section/Key words:Epigenetics: Inheritance of gene expression profiles independent of changes in DNA sequence or content.Histones: Small, basic proteins that package eukaryotic DNA into chromatin.Nucleosomes: Nucleosome core particles consist of an octamer of histone proteins (2x H2A, H2B, H3, H4) around which 147 bp of DNA are wrapped. Addition of linker DNA of various length and linker histones (H1) makes up the nucleosome as the basic, repeating unit of chromatin. DNA-Methylation:Enzymatic and none-enzymatic modification of DNA bases with methyl-groups.The methylation of C5 of cytosine is most relevant for gene regulation.Histone modifications: Chemical, posttranslational modifications of specific amino acids of histone proteins. The most abundant modifications are acetylation and methylation of the ε-amino group of lysines, methylation of the guanidino group of arginines and phosphorylation of hydroxyl groups in serines and threonines.Chemical probes: Synthetic molecules designed to interact with a protein of interest in order to study its function and activity.Cosubstrate probes: Chemical probes that are derived from the cellular small molecules that donate modifying groups to DNA and histones such as Adenosine triphosphate (ATP), Acetyl coenzyme A (acetyl-CoA) and S-adenosyl methionine (SAM).Substrate profiling: Proteomic approach to define the pool of target proteins of specific modifying enzymes using cosubstrate probes and mass spectrometry. 3 AbstractChromatin is the universal template of genetic information of all eukaryotic organisms. Chemical modifications of the DNA-packaging histone proteins and the DNA bases are crucial signaling events in directing the use and readout of eukaryotic genomes. The enzymes that install and remove these chromatin modifications as well as the proteins that bind these marks govern information that goes beyond the sequence of DNA. Therefore, these so called epigenetic regulators are intensively studied and represent promising drug targets in modern medicine. We summarize and discuss recent advances in the field of chemical biology that have provided chromatin research with sophisticated tools for investigating the composition, activity and target sites of chromatin modifying enzymes and reader proteins. 4In all eukaryotic cells chromatin, the complex of DNA and histone proteins regulates the functional state of the genome by altering condensation states and active recruitment of regulatory factors. The basic structural unit of chromatin is the nucleosome core particle. It consists of a protein core formed by two copies each of the histone proteins H2A, H2B, H3 and H4 with 147 base pairs of DNA wrapped around.1 Nucleosome core particles are connected by linker DNA, which can bind linker histones thereby giving rise to the fundamental repeating unit of chromatin, the nucleosome. Control of different chromatin states is mediated by a multitude of posttranslational modifications (PTMs) of the histone proteins, including methylation, acetylation and phosphorylatio...

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Analysis of Phosphorylation-Dependent Protein–Protein Interactions of Histone H3

Cited by 21 publications

References 51 publications

AMPK promotes mitochondrial biogenesis and function by phosphorylating the epigenetic factors DNMT1, RBBP7, and HAT1

AMPK promotes mitochondrial biogenesis and function by phosphorylating the epigenetic factors DNMT1, RBBP7, and HAT1

Rebelled epigenome: histone H3S10 phosphorylation and H3S10 kinases in cancer biology and therapy

Probing Chromatin-modifying Enzymes with Chemical Tools

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