ADP-ribose–derived nuclear ATP synthesis by NUDIX5 is required for chromatin remodeling

Wright, Roni H. G.; Lioutas, Antonios; Dily, François Le; Soronellas, Daniel; Pohl, Andy; Bonet, Jaume; Nacht, A. Silvina; Samino, Sara; Font-Mateu, Jofre; Vicent, Guillermo P.; Wierer, Michael; Trabado, Miriam A.; Schelhorn, Constanze; Carolis, Carlo; Macias, María J.; Yanes, Óscar; Oliva, Baldo; Beato, Miguel

doi:10.1126/science.aad9335

Cited by 156 publications

(188 citation statements)

References 23 publications

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“…Interestingly, a recent study proposed that PARP-1-generated PAR serves as a dynamic source of ATP, which is required for the activity of ATP-dependent chromatin remodeling enzymes during cellular signaling (Wright et al 2016). In this model, the pyrophosphatase NUDIX5 catalyzes the conversion of ADP-ribose to ATP in the presence of pyrophosphate.…”

Section: Parps In Gene Regulation: a Focus On Parp-1mentioning

confidence: 99%

“…This reaction, which was shown to be triggered in response to hormone-dependent signaling, enables the ATP generated to be used by chromatin remodeling enzymes to regulate hormone-dependent gene transcription ( Fig. 4A; Wright et al 2016).…”

Section: Parps In Gene Regulation: a Focus On Parp-1mentioning

confidence: 99%

“…The ATP generated is used by ATP-dependent chromatin remodeling enzymes to modulate nucleosome occupancy at progesterone receptor (PR) target genes to stimulate transcription (Wright et al 2016). (B) PARP-1 regulates the release of promoterproximally paused RNA polymerase II into productive transcriptional elongation through ADP-ribosylation of the negative elongation factor (NELF) complex.…”

Section: Parps In Gene Regulation: a Focus On Parp-1mentioning

confidence: 99%

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PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes

2017

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The discovery of poly(ADP-ribose) >50 years ago opened a new field, leading the way for the discovery of the poly(ADP-ribose) polymerase (PARP) family of enzymes and the ADP-ribosylation reactions that they catalyze. Although the field was initially focused primarily on the biochemistry and molecular biology of PARP-1 in DNA damage detection and repair, the mechanistic and functional understanding of the role of PARPs in different biological processes has grown considerably of late. This has been accompanied by a shift of focus from enzymology to a search for substrates as well as the first attempts to determine the functional consequences of site-specific ADP-ribosylation on those substrates. Supporting these advances is a host of methodological approaches from chemical biology, proteomics, genomics, cell biology, and genetics that have propelled new discoveries in the field. New findings on the diverse roles of PARPs in chromatin regulation, transcription, RNA biology, and DNA repair have been complemented by recent advances that link ADP-ribosylation to stress responses, metabolism, viral infections, and cancer. These studies have begun to reveal the promising ways in which PARPs may be targeted therapeutically for the treatment of disease. In this review, we discuss these topics and relate them to the future directions of the field.ADP-ribosylation is a reversible post-translational modification (PTM) of proteins resulting in the covalent attachment of a single ADP-ribose unit [i.e., mono(ADP-ribose) (MAR)] or polymers of ADP-ribose units [i.e., poly(ADP-ribose) (PAR)] on a variety of amino acid residues on target proteins (Gibson and Kraus 2012;Daniels et al. 2015a). This modification is mediated by a diverse group of ADPribosyl transferase (ADPRT) enzymes that use ADP-ribose units derived from β-NAD + to catalyze the ADP-ribosylation reaction. These enzymes include bacterial ADPRTs (e.g., cholera toxin and diphtheria toxin) as well as members of three different protein families in yeast and animals: (1) arginine-specific ecto-enzymes (ARTCs), (2) sirtuins, and (3) PAR polymerases (PARPs) . Surprisingly, a recent study showed that the bacterial toxin DarTG can ADP-ribosylate DNA . How this fits into the broader picture of cellular ADP-ribosylation has yet to be determined.In this review, we focus on the mono(ADP-ribosyl)ation (MARylation) and poly(ADP-ribosyl)ation (PARylation) of glutamate, aspartate, and lysine residues by PARP family members. While many reviews have been written on PARPs in the past decade, we highlight the current trends and ideas in the field, in particular those discoveries that have been published in the past 2-3 years.

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Section: Parps In Gene Regulation: a Focus On Parp-1mentioning

confidence: 99%

Section: Parps In Gene Regulation: a Focus On Parp-1mentioning

confidence: 99%

Section: Parps In Gene Regulation: a Focus On Parp-1mentioning

confidence: 99%

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PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes

2017

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“…To ensure very high levels of ATP production from carbohydrate and lipid oxidation, mitochondria increase their activity and number, resulting in enhanced release of reactive oxygen species (ROS) [98]. In close contact with the nucleus, which also produces ATP from the ADP-ribosyl residues after sudden extensive changes in chromatin [99] (perhaps the ones caused by the heterogeneous ribonucleoproteins (hnRNPs) identified in ALS) proteasome becomes especially important for maintaining cellular homeostasis through degradation of ubiquitinated factors like Drp1, which control mitochondria fusion and fission and the ubiquitinated misfolded ALS proteins [100]. In addition, reduced glucose uptake and metabolism consequent to increased glucocorticoid signaling pathways cannot be discarded [101][102][103].…”

Section: Energy Metabolism and Nutrition In Alsmentioning

confidence: 99%

Neuron-Microglia Interactions in Motor Neuron Degeneration. The Inflammatory Hypothesis in Amyotrophic Lateral Sclerosis Revisited

Rodrı́guez¹,

Mahy²

2016

CMC

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“…This result indicates that 2-oxo-ATP itself contributes to the reduction of intracellular ATP levels. However, there is the possibility that hMTH1 may increase intracellular ATP levels even if 2-oxo-ATP does not contribute to ATP depletion, because in the presence of pyrophosphates, which are produced during hydrolysis of 2-oxo-ATP by hMTH1, ATP is regenerated from ADP-ribose by NUDIX5 31 .…”

Section: Discussionmentioning

confidence: 99%

2-Oxoadenosine induces cytotoxicity through intracellular accumulation of 2-oxo-ATP and depletion of ATP but not via the p38 MAPK pathway

Asada

Ohta

Akimoto

et al. 2017

Sci Rep

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2-Oxoadenosine (2-oxo-Ado), an oxidized form of adenosine, is cytotoxic and induces growth arrest and cell death, which has potential as an anti-cancer drug. However, it is not well understood how 2-oxo-Ado exerts its cytotoxicity. We examined the effects of 2-oxo-Ado on non-tumour cells, namely immortalized mouse embryonic fibroblast lines, and investigated mechanisms by which 2-oxo-Ado exerts its cytotoxicity. We found that cell death induced by 2-oxo-Ado is classical caspase-dependent apoptosis, and requires its sequential intracellular phosphorylation catalysed by adenosine kinase (ADK) and adenylate kinase 2, resulting in intracellular accumulation of 2-oxo-ATP accompanied by accumulation of 2-oxo-Ado in RNA and depletion of ATP. Moreover, we showed that overexpression of MTH1, an oxidized purine nucleoside triphosphatase, prevents 2-oxo-Ado-induced cytotoxicity accompanied by suppression of accumulation of both intracellular 2-oxo-ATP and 2-oxo-Ado in RNA and recovery of ATP levels. We also found that 2-oxo-Ado activates the p38 MAPK pathway. However, siRNAs against Mkk3 and Mkk6, or treatment with several p38 MAPK inhibitors, except SB203580, did not prevent the cytotoxicity. SB203580 prevented intracellular phosphorylation of 2-oxo-Ado to 2-oxo-AMP, and an in vitro ADK assay revealed that SB203580 directly inhibits ADK activity, suggesting that some of the effects of SB203580 may depend on ADK inhibition.

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ADP-ribose–derived nuclear ATP synthesis by NUDIX5 is required for chromatin remodeling

Cited by 156 publications

References 23 publications

PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes

PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes

Neuron-Microglia Interactions in Motor Neuron Degeneration. The Inflammatory Hypothesis in Amyotrophic Lateral Sclerosis Revisited

2-Oxoadenosine induces cytotoxicity through intracellular accumulation of 2-oxo-ATP and depletion of ATP but not via the p38 MAPK pathway

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