Systems Biology Approach Identifies the Kinase Csnk1a1 as a Regulator of the DNA Damage Response in Embryonic Stem Cells

Carreras-Puigvert, Jordi; Stechow, Louise von; Siddappa, Ramakrishnaiah; Pines, Alex; Bahjat, Mahnoush; Haazen, Lizette C. J. M.; Olsen, Jesper V.; Vrieling, Harry; Meerman, John H.N.; Mullenders, Leon H.F.; Water, Bob van de; Danen, Erik H.J.

doi:10.1126/scisignal.2003208

Cited by 30 publications

(18 citation statements)

References 50 publications

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“…Interestingly, a number of metabolic enzymes we find to be transcriptionally modified by cisplatin are target genes of the key DDR transcriptional regulator, p53. This is in agreement with our recent finding that p53 is a major DDR signaling hub in ES cells [12]. Moreover, the integration of transcriptionally regulated metabolic enzymes and significantly affected metabolites allows identification of integrated metabolic networks that are responsive to genotoxic stress.…”

Section: Discussionsupporting

confidence: 92%

“…Transcriptional microarray data have been published [12] and are available from ArrayExpress. HM1 ES cells were treated with 10 µM cisplatin or vehicle control for 8 hours in three independent experiments.…”

Section: Methodsmentioning

confidence: 99%

“…Next to direct DNA damage, cisplatin also induces non-genotoxic perturbations, such as oxidative stress by shifting the redox balance through binding to nucleophilic molecules; and ER stress, which has been shown to kill enucleated cells [10], [11]. We have unraveled cisplatin-responsive signaling networks in mouse embryonic stem (ES) cells through integration of functional genomics, phosphoproteomics, and transcriptomics [12], [13]. These studies point to a major role for DNA damage response (DDR) signaling in determining the cellular outcome of cisplatin treatment.…”

Section: Introductionmentioning

confidence: 99%

“…We decided to make use of ES cells to study the DDR using systems wide analyses [12], [13]. These cells have an intact, effective DDR and show robust DNA damage-induced apoptosis.…”

Section: Introductionmentioning

confidence: 99%

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Identification of Cisplatin-Regulated Metabolic Pathways in Pluripotent Stem Cells

et al. 2013

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The chemotherapeutic compound, cisplatin causes various kinds of DNA lesions but also triggers other pertubations, such as ER and oxidative stress. We and others have shown that treatment of pluripotent stem cells with cisplatin causes a plethora of transcriptional and post-translational alterations that, to a major extent, point to DNA damage response (DDR) signaling. The orchestrated DDR signaling network is important to arrest the cell cycle and repair the lesions or, in case of damage beyond repair, eliminate affected cells. Failure to properly balance the various aspects of the DDR in stem cells contributes to ageing and cancer. Here, we performed metabolic profiling by mass spectrometry of embryonic stem (ES) cells treated for different time periods with cisplatin. We then integrated metabolomics with transcriptomics analyses and connected cisplatin-regulated metabolites with regulated metabolic enzymes to identify enriched metabolic pathways. These included nucleotide metabolism, urea cycle and arginine and proline metabolism. Silencing of identified proline metabolic and catabolic enzymes indicated that altered proline metabolism serves as an adaptive, rather than a toxic response. A group of enriched metabolic pathways clustered around the metabolite S-adenosylmethionine, which is a hub for methylation and transsulfuration reactions and polyamine metabolism. Enzymes and metabolites with pro- or anti-oxidant functions were also enriched but enhanced levels of reactive oxygen species were not measured in cisplatin-treated ES cells. Lastly, a number of the differentially regulated metabolic enzymes were identified as target genes of the transcription factor p53, pointing to p53-mediated alterations in metabolism in response to genotoxic stress. Altogether, our findings reveal interconnecting metabolic pathways that are responsive to cisplatin and may serve as signaling modules in the DDR in pluripotent stem cells.

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Section: Discussionsupporting

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…We decided to make use of ES cells to study the DDR using systems wide analyses [12], [13]. These cells have an intact, effective DDR and show robust DNA damage-induced apoptosis.…”

Section: Introductionmentioning

confidence: 99%

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Identification of Cisplatin-Regulated Metabolic Pathways in Pluripotent Stem Cells

et al. 2013

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“…1, 2, 3 The success of these technologies has already been demonstrated in biomedicine by the discovery of new pathways and drug targets not evident from classical examinations. 4, 5, 6 Such investigations have not yet been reported in neurotoxicology, but transcriptomics and metabolomics profiling are being increasingly used in related fields such as developmental toxicology. 7, 8, 9, 10 Re-examination of established toxicants is essential to test the feasibility of new approaches and to gain knowledge about how and when they are best applied.…”

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confidence: 99%

Transcriptional and metabolic adaptation of human neurons to the mitochondrial toxicant MPP+

et al. 2014

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Assessment of the network of toxicity pathways by Omics technologies and bioinformatic data processing paves the road toward a new toxicology for the twenty-first century. Especially, the upstream network of responses, taking place in toxicant-treated cells before a point of no return is reached, is still little explored. We studied the effects of the model neurotoxicant 1-methyl-4-phenylpyridinium (MPP+) by a combined metabolomics (mass spectrometry) and transcriptomics (microarrays and deep sequencing) approach to provide unbiased data on earliest cellular adaptations to stress. Neural precursor cells (LUHMES) were differentiated to homogeneous cultures of fully postmitotic human dopaminergic neurons, and then exposed to the mitochondrial respiratory chain inhibitor MPP+ (5 μM). At 18–24 h after treatment, intracellular ATP and mitochondrial integrity were still close to control levels, but pronounced transcriptome and metabolome changes were seen. Data on altered glucose flux, depletion of phosphocreatine and oxidative stress (e.g., methionine sulfoxide formation) confirmed the validity of the approach. New findings were related to nuclear paraspeckle depletion, as well as an early activation of branches of the transsulfuration pathway to increase glutathione. Bioinformatic analysis of our data identified the transcription factor ATF-4 as an upstream regulator of early responses. Findings on this signaling pathway and on adaptive increases of glutathione production were confirmed biochemically. Metabolic and transcriptional profiling contributed complementary information on multiple primary and secondary changes that contribute to the cellular response to MPP+. Thus, combined ‘Omics' analysis is a new unbiased approach to unravel earliest metabolic changes, whose balance decides on the final cell fate.

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Therapeutic Targetingof the Wnt Signaling Network

Rudge

Dale

2014

WNT Signaling in Development and Disease

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Systems Biology Approach Identifies the Kinase Csnk1a1 as a Regulator of the DNA Damage Response in Embryonic Stem Cells

Cited by 30 publications

References 50 publications

Identification of Cisplatin-Regulated Metabolic Pathways in Pluripotent Stem Cells

Identification of Cisplatin-Regulated Metabolic Pathways in Pluripotent Stem Cells

Transcriptional and metabolic adaptation of human neurons to the mitochondrial toxicant MPP+

Therapeutic Targetingof the Wnt Signaling Network

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