A macrodomain-containing histone rearranges chromatin upon sensing PARP1 activation

Timinszky, Gyula; Till, Susanne; Hassa, Paul O.; Hothorn, Michael; Kustatscher, Georg; Nijmeijer, Bianca; Colombelli, Julien; Altmeyer, Matthias; Stelzer, Ernst H. K.; Scheffzek, Klaus; Hottiger, Michael O.; Ladurner, Andreas G.

doi:10.1038/nsmb.1664

Cited by 394 publications

(458 citation statements)

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“…On the basis of all known PAR-binding motifs or domains, such as the PBZ motif 32 , eight amino-acid motif 30 and macrodomains [34][35][36] , we blasted the databases (Ensembl; http://www.ensembl.org/index.html, RCSB Protein Data Bank http://www.pdb.org/pdb/home/home.do and ExPASy http://www.expasy.org/) but did not find any of these motifs in Chk1. However, we detected a putative C2H2 motif (C 8 -C 6 -H 8 -H) in the amino terminus of Chk1, which is distinct from the canonical PBZ C2H2 (C 8 -C 8 -H 8 -H) but displays a strong regularity of amino-acid sequences (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…To date, three PAR-binding motifs have been identified in various proteins, including the putative consensus sequence of an eight amino-acid motif 30,31 , the PAR-binding zinc-finger (PBZ) motif 32,33 and the macrodomains [34][35][36] . Despite the universal nature of the poly(ADP-ribosyl)ation of target proteins, and PARP's function in a wide range of cellular activities 21,25 , only a limited number of PAR-binding motifs have been found in several target proteins 20,37 .…”

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confidence: 99%

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Poly(ADP-ribose) binding to Chk1 at stalled replication forks is required for S-phase checkpoint activation

et al. 2013

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Damaged replication forks activate poly(ADP-ribose) polymerase 1 (PARP1), which catalyses poly(ADP-ribose) (PAR) formation; however, how PARP1 or poly(ADP-ribosyl)ation is involved in the S-phase checkpoint is unknown. Here we show that PAR, supplied by PARP1, interacts with Chk1 via a novel PAR-binding regulatory (PbR) motif in Chk1, independent of ATR and its activity. iPOND studies reveal that Chk1 associates readily with the unperturbed replication fork and that PAR is required for efficient retention of Chk1 and phosphorylated Chk1 at the fork. A PbR mutation, which disrupts PAR binding, but not the interaction with its partners Claspin or BRCA1, impairs Chk1 and the S-phase checkpoint activation, and mirrors Chk1 knockdown-induced hypersensitivity to fork poisoning. We find that long chains, but not short chains, of PAR stimulate Chk1 kinase activity. Collectively, we disclose a previously unrecognized mechanism of the S-phase checkpoint by PAR metabolism that modulates Chk1 activity at the replication fork.

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Section: Resultsmentioning

confidence: 99%

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Poly(ADP-ribose) binding to Chk1 at stalled replication forks is required for S-phase checkpoint activation

et al. 2013

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“…PARP1 activation recruits histone macroH2A and the chromatin remodelling enzyme ALC1 to the site of damage. Around the damaged site they facilitate sitespecific DNA repair via chromatin relaxation [40,41].…”

Section: Reviewmentioning

confidence: 99%

Regulatory crosstalk of the metabolic network

Grüning

Lehrach

Ralser

2010

Trends in Biochemical Sciences

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The metabolic network has a modular architecture, is robust to perturbations, and responds to biological stimuli and environmental conditions. Through monitoring by metabolite responsive macromolecules, metabolic pathways interact with the transcriptome and proteome. Whereas pathway interconnecting cofactors and substrates report on the overall state of the network, specialised intermediates measure the activity of individual functional units. Transitions in the network affect many of these regulatory metabolites, facilitating the parallel regulation of the timing and control of diverse biological processes. The metabolic network controls its own balance, chromatin structure and the biosynthesis of molecular cofactors; moreover, metabolic shifts are crucial in the response to oxidative stress and play a regulatory role in cancer.Evolution of the metabolic network and its structure Life probably began with the formation of compartmentalised autocatalytic chemical cycles. With the appearance of complex catalysts (ribonucleic acid-or protein-based enzymes), these cycles gained complexity, and evolved in their effectiveness and robustness [1]. These metabolic pathways now form the basis for life.As was the case for the first primitive life forms, the survival of today's complex organisms depends on the robustness and functionality of the metabolic framework [2]. To prevent and counteract perturbations in the flux, many biological control and sensor systems have evolved around the metabolic network. Metabolic pathways provide the cell with energy and supply macromolecular synthesis pathways with their required intermediates. They also balance metabolic systems under a variety of physiological conditions, and act as transducers and sensor systems for environmental conditions and stimuli. In addition, metabolic pathways are essential for crosstalk between metabolic regulatory components and the cellular transcriptome and proteome.As early as the 1960s, the principle that cells alter their gene expression in response to metabolic requirements has been known. The seminal work of Jacob and Monod, investigating the lac operon, uncovered one of the first examples of chemical-genetic regulation, by which bacterial cells adjust their enzyme production to the nutrient supply [3]. However, only recently have the broader implications of this principle emerged. Indeed, changes in the metabolic network not only control the metabolome, but they also have wide-ranging regulatory functions throughout biology.Most of the biochemical mechanisms that link the metabolic network to the transcriptome and proteome are incompletely understood. However, one type of regulation appears to be common: representative network intermediates bind to and modulate sensor function and activity of transcription factors, translational regulators, chromatin, enzymes, RNA molecules, and ion channels. Significant transcriptional changes around these intermediates identified them as reporter metabolites [4,5]. The use of intermediates as activity reporters ne...

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“…PARylation regulates various cellular processes, such as DNA repair, specific signalling processes and gene transcription 5 . The functional consequences of PARylation are mediated by distinct protein domains, including macrodomains, WWE (named after two conserved tryptophan residues and a glutamate residue) and PAR-binding zinc-finger (PBZ) domains [6][7][8][9][10] . In contrast to the function of class 1 ARTD enzyme-mediated PARylation, little is known about the biological relevance of mono-ADP-ribosyltransferases.…”

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Regulation of NF-κB signalling by the mono-ADP-ribosyltransferase ARTD10

et al. 2013

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Adenosine diphosphate-ribosylation is a post-translational modification mediated by intracellular and membrane-associated extracellular enzymes and many bacterial toxins. The intracellular enzymes modify their substrates either by poly-ADP-ribosylation, exemplified by ARTD1/PARP1, or by mono-ADP-ribosylation. The latter has been discovered only recently, and little is known about its physiological relevance. The founding member of mono-ADPribosyltransferases is ARTD10/PARP10. It possesses two ubiquitin-interaction motifs, a unique feature among ARTD/PARP enzymes. Here, we find that the ARTD10 ubiquitininteraction motifs bind to K63-linked poly-ubiquitin, a modification that is essential for NF-kB signalling. We therefore studied the role of ARTD10 in this pathway. ARTD10 inhibits the activation of NF-kB and downstream target genes in response to interleukin-1b and tumour necrosis factor-a, dependent on catalytic activity and poly-ubiquitin binding of ARTD10. Mechanistically ARTD10 interferes with poly-ubiquitination of NEMO, which interacts with and is a substrate of ARTD10. Our findings identify a novel regulator of NF-kB signalling and provide evidence for cross-talk between K63-linked poly-ubiquitination and mono-ADPribosylation.

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A macrodomain-containing histone rearranges chromatin upon sensing PARP1 activation

Cited by 394 publications

References 40 publications

Poly(ADP-ribose) binding to Chk1 at stalled replication forks is required for S-phase checkpoint activation

Poly(ADP-ribose) binding to Chk1 at stalled replication forks is required for S-phase checkpoint activation

Regulatory crosstalk of the metabolic network

Regulation of NF-κB signalling by the mono-ADP-ribosyltransferase ARTD10

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