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Article ; Online: NFATC2IP is a mediator of SUMO-dependent genome integrity.

Cho, Tiffany / Hoeg, Lisa / Setiaputra, Dheva / Durocher, Daniel

2024 Volume 38, Issue 5-6, Page(s) 233–252

Abstract: The post-translational modification of proteins by SUMO is crucial for cellular viability and mammalian development in part due to the contribution of SUMOylation to genome duplication and repair. To investigate the mechanisms underpinning the essential ... ...

Abstract	The post-translational modification of proteins by SUMO is crucial for cellular viability and mammalian development in part due to the contribution of SUMOylation to genome duplication and repair. To investigate the mechanisms underpinning the essential function of SUMO, we undertook a genome-scale CRISPR/Cas9 screen probing the response to SUMOylation inhibition. This effort identified 130 genes whose disruption reduces or enhances the toxicity of TAK-981, a clinical-stage inhibitor of the SUMO E1-activating enzyme. Among the strongest hits, we validated and characterized NFATC2IP, an evolutionarily conserved protein related to the fungal Esc2 and Rad60 proteins that harbors tandem SUMO-like domains. Cells lacking NFATC2IP are viable but are hypersensitive to SUMO E1 inhibition, likely due to the accumulation of mitotic chromosome bridges and micronuclei. NFATC2IP primarily acts in interphase and associates with nascent DNA, suggesting a role in the postreplicative resolution of replication or recombination intermediates. Mechanistically, NFATC2IP interacts with the SMC5/6 complex and UBC9, the SUMO E2, via its first and second SUMO-like domains, respectively. AlphaFold-Multimer modeling suggests that NFATC2IP positions and activates the UBC9-NSMCE2 complex, the SUMO E3 ligase associated with SMC5/SMC6. We conclude that NFATC2IP is a key mediator of SUMO-dependent genomic integrity that collaborates with the SMC5/6 complex.
MeSH term(s)	Cell Cycle Proteins/metabolism ; DNA Damage ; Sumoylation ; Ubiquitin-Protein Ligases/metabolism ; Humans ; Genomic Instability/genetics
Chemical Substances	Cell Cycle Proteins ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; NFATC2IP protein, human
Language	English
Publishing date	2024-04-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	806684-x
ISSN	1549-5477 ; 0890-9369
ISSN (online)	1549-5477
ISSN	0890-9369
DOI	10.1101/gad.350914.123
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Zs.A 2292: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 54: Show issues

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Article ; Online: The development and characterization of a CRISPR/Cas9-mediated PD-1 functional knockout rat as a tool to study idiosyncratic drug reactions.

Cho, Tiffany / Wierk, Antonia / Gertsenstein, Marina / Rodgers, Christopher E / Uetrecht, Jack / Henderson, Jeffrey T

Toxicological sciences : an official journal of the Society of Toxicology

2024 Volume 198, Issue 2, Page(s) 233–245

Abstract: Idiosyncratic drug reactions are rare but serious adverse drug reactions unrelated to the known therapeutic properties of the drug and manifest in only a small percentage of the treated population. Animal models play an important role in advancing ... ...

Abstract	Idiosyncratic drug reactions are rare but serious adverse drug reactions unrelated to the known therapeutic properties of the drug and manifest in only a small percentage of the treated population. Animal models play an important role in advancing mechanistic studies examining idiosyncratic drug reactions. However, to be useful, they must possess similarities to those seen clinically. Although mice currently represent the dominant mammalian genetic model, rats are advantageous in many areas of pharmacologic study where their physiology can be examined in greater detail and is more akin to that seen in humans. In the area of immunology, this includes autoimmune responses and susceptibility to diabetes, in which rats more accurately mimic disease states in humans compared with mice. For example, oral nevirapine treatment can induce an immune-mediated skin rash in humans and rats, but not in mice due to the absence of the sulfotransferase required to form reactive metabolites of nevirapine within the skin. Using CRISPR-mediated gene editing, we developed a modified line of transgenic rats in which a segment of IgG-like ectodomain containing the core PD-1 interaction motif containing the native ligand and therapeutic antibody domain in exon 2 was deleted. Removal of this region critical for mediating PD-1/PD-L1 interactions resulted in animals with an increased immune response resulting in liver injury when treated with amodiaquine.
MeSH term(s)	Humans ; Rats ; Mice ; Animals ; Nevirapine/toxicity ; Nevirapine/metabolism ; Programmed Cell Death 1 Receptor/metabolism ; CRISPR-Cas Systems ; Models, Animal ; Liver/metabolism ; Drug-Related Side Effects and Adverse Reactions ; Mammals/metabolism
Chemical Substances	Nevirapine (99DK7FVK1H) ; Programmed Cell Death 1 Receptor
Language	English
Publishing date	2024-01-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	1420885-4
ISSN	1096-0929 ; 1096-6080
ISSN (online)	1096-0929
ISSN	1096-6080
DOI	10.1093/toxsci/kfae003
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Article ; Online: Testing Possible Risk Factors for Idiosyncratic Drug-Induced Liver Injury Using an Amodiaquine Mouse Model and Co-treatment with 1-Methyl-d-Tryptophan or Acetaminophen.

Cho, Tiffany / Kok, Lie Yun / Uetrecht, Jack

ACS omega

2021 Volume 6, Issue 7, Page(s) 4656–4662

Abstract: Idiosyncratic drug reactions are unpredictable adverse reactions. Although most such adverse reactions appear to be immune mediated, their exact mechanism(s) remain elusive. The idiosyncratic drug reaction most associated with serious consequences is ... ...

Abstract	Idiosyncratic drug reactions are unpredictable adverse reactions. Although most such adverse reactions appear to be immune mediated, their exact mechanism(s) remain elusive. The idiosyncratic drug reaction most associated with serious consequences is idiosyncratic drug-induced liver injury (IDILI). We have developed a mouse model of amodiaquine (AQ)-induced liver injury that reflects the clinical characteristics of IDILI in humans. This was accomplished by impairing immune tolerance by using PD-1
Language	English
Publishing date	2021-02-07
Publishing country	United States
Document type	Journal Article
ISSN	2470-1343
ISSN (online)	2470-1343
DOI	10.1021/acsomega.0c05352
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Article ; Online: Response to the Letter to the Editor Concerning the Article "Rotenone Increases Isoniazid Toxicity but Does Not Cause Liver Injury: Implications for the Hypothesis That Inhibition of the Mitochondrial Electron Transport Chain Is a Common Mechanism of Idiosyncratic Drug-Induced Liver Injury" by Bernard Fromenty.

Cho, Tiffany / Uetrecht, Jack

Chemical research in toxicology

2019 Volume 33, Issue 1, Page(s) 5–6

MeSH term(s)	Chemical and Drug Induced Liver Injury ; Electron Transport ; Humans ; Isoniazid ; Rotenone
Chemical Substances	Rotenone (03L9OT429T) ; Isoniazid (V83O1VOZ8L)
Language	English
Publishing date	2019-12-17
Publishing country	United States
Document type	Letter ; Comment
ZDB-ID	639353-6
ISSN	1520-5010 ; 0893-228X
ISSN (online)	1520-5010
ISSN	0893-228X
DOI	10.1021/acs.chemrestox.9b00436
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Article ; Online: Liver Injury Caused by Green Tea Extract in PD-1

Cho, Tiffany / Wang, Xijin / Yeung, Karen / Cao, Yanshan / Uetrecht, Jack

Chemical research in toxicology

2021 Volume 34, Issue 3, Page(s) 849–856

Abstract: Idiosyncratic drug-induced liver injury (IDILI) is an idiosyncratic drug reaction that is specific to an individual and can lead to liver failure and even death. The mechanism of IDILI remains poorly understood, but most IDILI appears to be immune- ... ...

Abstract	Idiosyncratic drug-induced liver injury (IDILI) is an idiosyncratic drug reaction that is specific to an individual and can lead to liver failure and even death. The mechanism of IDILI remains poorly understood, but most IDILI appears to be immune-mediated. We have developed the first validated animal model by using a PD-1
MeSH term(s)	Animals ; Catechin/chemistry ; Catechin/pharmacology ; Chemical and Drug Induced Liver Injury/immunology ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Female ; Immune Tolerance/drug effects ; Liver/drug effects ; Liver/immunology ; Liver/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Plant Extracts/chemistry ; Plant Extracts/pharmacology ; Programmed Cell Death 1 Receptor/antagonists & inhibitors ; Programmed Cell Death 1 Receptor/deficiency ; Programmed Cell Death 1 Receptor/immunology ; Tea/chemistry
Chemical Substances	Pdcd1 protein, mouse ; Plant Extracts ; Programmed Cell Death 1 Receptor ; Tea ; Catechin (8R1V1STN48)
Language	English
Publishing date	2021-02-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639353-6
ISSN	1520-5010 ; 0893-228X
ISSN (online)	1520-5010
ISSN	0893-228X
DOI	10.1021/acs.chemrestox.0c00485
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Article ; Online: The Putative Drosophila TMEM184B Ortholog Tmep Ensures Proper Locomotion by Restraining Ectopic Firing at the Neuromuscular Junction.

Cho, Tiffany S / Beigaitė, Eglė / Klein, Nathaniel E / Sweeney, Sean T / Bhattacharya, Martha R C

Molecular neurobiology

2022 Volume 59, Issue 4, Page(s) 2605–2619

Abstract: TMEM184B is a putative seven-pass membrane protein that promotes axon degeneration after injury. TMEM184B mutation causes aberrant neuromuscular architecture and sensory and motor behavioral defects in mice. The mechanism through which TMEM184B causes ... ...

Abstract	TMEM184B is a putative seven-pass membrane protein that promotes axon degeneration after injury. TMEM184B mutation causes aberrant neuromuscular architecture and sensory and motor behavioral defects in mice. The mechanism through which TMEM184B causes neuromuscular defects is unknown. We employed Drosophila melanogaster to investigate the function of the closely related gene, Tmep (CG12004), at the neuromuscular junction. We show that Tmep is required for full adult viability and efficient larval locomotion. Tmep mutant larvae have a reduced body contraction rate compared to controls, with stronger deficits in females. In recordings from body wall muscles, Tmep mutants show substantial hyperexcitability, with many postsynaptic potentials fired in response to a single stimulation, consistent with a role for Tmep in restraining synaptic excitability. Additional branches and satellite boutons at Tmep mutant neuromuscular junctions are consistent with an activity-dependent synaptic overgrowth. Tmep is expressed in endosomes and synaptic vesicles within motor neurons, suggesting a possible role in synaptic membrane trafficking. Using RNAi knockdown, we show that Tmep is required in motor neurons for proper larval locomotion and excitability, and that its reduction increases levels of presynaptic calcium. Locomotor defects can be rescued by presynaptic knockdown of endoplasmic reticulum calcium channels or by reducing evoked release probability, further suggesting that excess synaptic activity drives behavioral deficiencies. Our work establishes a critical function for Tmep in the regulation of synaptic transmission and locomotor behavior.
MeSH term(s)	Animals ; Drosophila/metabolism ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; Drosophila melanogaster/metabolism ; Larva/metabolism ; Locomotion/genetics ; Mice ; Neuromuscular Junction/metabolism ; Presynaptic Terminals/metabolism ; Synaptic Transmission/physiology
Chemical Substances	Drosophila Proteins
Language	English
Publishing date	2022-02-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	645020-9
ISSN	1559-1182 ; 0893-7648
ISSN (online)	1559-1182
ISSN	0893-7648
DOI	10.1007/s12035-022-02760-3
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Zs.A 2411: Show issues

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Article ; Online: How Reactive Metabolites Induce an Immune Response That Sometimes Leads to an Idiosyncratic Drug Reaction.

Cho, Tiffany / Uetrecht, Jack

Chemical research in toxicology

2017 Volume 30, Issue 1, Page(s) 295–314

Abstract: Little is known with certainty about the mechanisms of idiosyncratic drug reactions (IDRs); however, there is substantive evidence that reactive metabolites are involved in most, but not all, IDRs. In addition, evidence also suggests that most IDRs are ... ...

Abstract	Little is known with certainty about the mechanisms of idiosyncratic drug reactions (IDRs); however, there is substantive evidence that reactive metabolites are involved in most, but not all, IDRs. In addition, evidence also suggests that most IDRs are immune mediated. That raises the question of how reactive metabolites induce an immune response that can lead to an IDR. The dominant hypotheses are the hapten and danger hypotheses. These are complementary hypotheses: a reactive metabolite can act as a hapten to produce neoantigens, and it can also cause cell damage leading to the release of danger-associated molecular pattern molecules that activate antigen presenting cells. Both are required for an immune response. In addition, drugs may induce an immune response through inflammasome activation. We have found examples in which the ability to activate inflammasomes differentiated drugs that cause IDRs from similar drugs that do not. There are other hypotheses that do not involve an immune mechanism such as mitochondrial injury and bile salt export pump (BSEP) inhibition. With some possible exceptions, these hypotheses are unlikely to be able to completely explain IDRs. However, some types of mitochondrial injury or BSEP inhibition could produce danger signals. The major mechanism that protects us from IDRs appears to be immune tolerance. Consistent with this hypothesis, we used checkpoint inhibition to develop the first animal model of idiosyncratic drug-induced liver injury that has the same characteristics as the idiosyncratic injury in humans. This was accomplished by treating Pd-1
MeSH term(s)	Animals ; Drug-Related Side Effects and Adverse Reactions/immunology ; Drug-Related Side Effects and Adverse Reactions/metabolism ; Humans ; Immune Tolerance ; Pharmaceutical Preparations/metabolism ; Risk Factors
Chemical Substances	Pharmaceutical Preparations
Language	English
Publishing date	2017--17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	639353-6
ISSN	1520-5010 ; 0893-228X
ISSN (online)	1520-5010
ISSN	0893-228X
DOI	10.1021/acs.chemrestox.6b00357
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Article ; Online: Rotenone Increases Isoniazid Toxicity but Does Not Cause Significant Liver Injury: Implications for the Hypothesis that Inhibition of the Mitochondrial Electron Transport Chain Is a Common Mechanism of Idiosyncratic Drug-Induced Liver Injury.

Cho, Tiffany / Wang, Xijin / Uetrecht, Jack

Chemical research in toxicology

2019 Volume 32, Issue 7, Page(s) 1423–1431

Abstract: Idiosyncratic drug reactions (IDRs) significantly increase the risk of failure in drug development. The major IDR leading to drug candidate failure is idiosyncratic drug-induced liver injury (IDILI). Although most evidence suggests that IDRs are mediated ...

Abstract	Idiosyncratic drug reactions (IDRs) significantly increase the risk of failure in drug development. The major IDR leading to drug candidate failure is idiosyncratic drug-induced liver injury (IDILI). Although most evidence suggests that IDRs are mediated by the immune system, there are other hypotheses, such as mitochondrial dysfunction. Many pharmaceutical companies routinely screen for mitochondrial toxicity in an attempt to "derisk" drug candidates. However, the basic hypothesis has never been rigorously tested. A major assay used for this screening involves measurement of inhibition of the mitochondrial electron transport chain. One study found that the combination of rotenone and isoniazid, which inhibit mitochondrial complex I and II, respectively, were synergistic in causing hepatocyte toxicity in vitro and suggested the combination of another drug that inhibited complex I would increase the risk of isoniazid-induced liver injury in patients. We tested this hypothesis in vivo where wild-type and PD-1-/- mice administered anti-CTLA-4, our impaired immune tolerance mouse model, were given 0.02% (w/v) rotenone in water or 0.1%, 0.05%, and 0.01% (w/w) rotenone alone or in combination with isoniazid in food. The cotreatment led to lethality in 100% of the animals receiving 0.1% rotenone and 0.2% isoniazid and 83% of the animals cotreated with 0.05% rotenone and 0.2% isoniazid in food. Nevertheless, there was no significant increase in GLDH or histological evidence of liver injury. No signs of toxicity were observed in any of the mice given rotenone or isoniazid alone. Even though inhibition of the mitochondrial electron transport chain did not lead to significant liver toxicity, it could provide danger signals that promote immune-mediated liver injury. However, rotenone did not significantly increase the liver injury induced by isoniazid in our impaired immune tolerance model. Overall, we conclude that inhibition of the mitochondrial electron transport chain is not a significant mechanism of IDILI.
MeSH term(s)	Animals ; Chemical and Drug Induced Liver Injury/etiology ; Drug Synergism ; Electron Transport/drug effects ; Electron Transport Complex I/antagonists & inhibitors ; Electron Transport Complex II/antagonists & inhibitors ; Enzyme Inhibitors/toxicity ; Female ; Isoniazid/toxicity ; Liver/drug effects ; Mice, Inbred C57BL ; Mitochondria/drug effects ; Rotenone/toxicity
Chemical Substances	Enzyme Inhibitors ; Rotenone (03L9OT429T) ; Electron Transport Complex II (EC 1.3.5.1) ; Electron Transport Complex I (EC 7.1.1.2) ; Isoniazid (V83O1VOZ8L)
Language	English
Publishing date	2019-06-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639353-6
ISSN	1520-5010 ; 0893-228X
ISSN (online)	1520-5010
ISSN	0893-228X
DOI	10.1021/acs.chemrestox.9b00116
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Article ; Online: Use of an animal model to test whether non-alcoholic fatty liver disease increases the risk of idiosyncratic drug-induced liver injury.

Mak, Alastair / Cho, Tiffany / Uetrecht, Jack

Journal of immunotoxicology

2018 Volume 15, Issue 1, Page(s) 90–95

Abstract: Clinical evidence suggests that most idiosyncratic drug-induced liver injury (IDILI) is immune-mediated. The danger hypothesis suggests that liver injury and inflammation would increase the risk of an immune response leading to IDILI. Therefore, a ... ...

Abstract	Clinical evidence suggests that most idiosyncratic drug-induced liver injury (IDILI) is immune-mediated. The danger hypothesis suggests that liver injury and inflammation would increase the risk of an immune response leading to IDILI. Therefore, a reasonable hypothesis would be that an underlying chronic liver disease such as non-alcoholic steatohepatitis (NASH) would increase the risk of developing IDILI due to inflammation and release of danger signals from damaged cells. In order to test this hypothesis, mice were fed a methionine-/choline-deficient (MCD) diet that produces a consistent NASH phenotype, along with amodiaquine (AQ) - a drug known to cause IDILI in humans. This study employed both wild-type C57BL/6 mice and PD-1
MeSH term(s)	Amodiaquine ; Animals ; Antibodies, Blocking/administration & dosage ; Chemical and Drug Induced Liver Injury/immunology ; Choline Deficiency ; Disease Models, Animal ; Female ; Granzymes ; Humans ; Inflammation/immunology ; Liver/drug effects ; Liver/immunology ; Methionine/deficiency ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Non-alcoholic Fatty Liver Disease/immunology ; Programmed Cell Death 1 Receptor/genetics ; Risk
Chemical Substances	Antibodies, Blocking ; Pdcd1 protein, mouse ; Programmed Cell Death 1 Receptor ; Amodiaquine (220236ED28) ; Methionine (AE28F7PNPL) ; Granzymes (EC 3.4.21.-) ; Gzmb protein, mouse (EC 3.4.21.-)
Language	English
Publishing date	2018-05-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2205064-4
ISSN	1547-6901 ; 1547-691X
ISSN (online)	1547-6901
ISSN	1547-691X
DOI	10.1080/1547691X.2018.1467982
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Article ; Online: The Effects of Immune Modulators on Amodiaquine-Induced Liver Injury.

Mak, Alastair / Cho, Tiffany Elizabeth / Uetrecht, Jack

Chemical research in toxicology

2018 Volume 31, Issue 8, Page(s) 739–744

Abstract: If idiosyncratic drug-induced liver injury (IDILI) is immune mediated, then it is logical that immune modulators may be able to affect liver injury caused by a drug. We have previously shown that modulating the immune system by impairing programmed cell ... ...

Abstract	If idiosyncratic drug-induced liver injury (IDILI) is immune mediated, then it is logical that immune modulators may be able to affect liver injury caused by a drug. We have previously shown that modulating the immune system by impairing programmed cell death protein (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) signaling, both receptors involved in immune tolerance, was capable of producing an animal model of amodiaquine (AQ) IDILI with characteristics very similar to IDILI in humans. Other immune modulators may also increase liver injury caused by drugs that cause IDILI in humans. In this study, myeloid derived suppressor cells (MDSCs), transforming growth factor beta (TGF-β), and lymphocyte-activation gene 3 (LAG3) were targeted with antibodies, with and without PD-1 and CTLA-4 impairment. We found that anti-Gr1 antibodies used to deplete MDSCs led to a significant increase in AQ-induced liver injury in wild-type mice; however, the injury was actually less in PD-1
MeSH term(s)	Adjuvants, Immunologic/pharmacology ; Amodiaquine/toxicity ; Animals ; Antimalarials/toxicity ; CTLA-4 Antigen/metabolism ; Chemical and Drug Induced Liver Injury ; Female ; Humans ; Mice ; Mice, Inbred C57BL ; Programmed Cell Death 1 Receptor/metabolism ; Signal Transduction
Chemical Substances	Adjuvants, Immunologic ; Antimalarials ; CTLA-4 Antigen ; Programmed Cell Death 1 Receptor ; Amodiaquine (220236ED28)
Language	English
Publishing date	2018-07-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639353-6
ISSN	1520-5010 ; 0893-228X
ISSN (online)	1520-5010
ISSN	0893-228X
DOI	10.1021/acs.chemrestox.8b00091
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