Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIEU9NH)

• DOT Name: MRN complex-interacting protein (MRNIP)
• Synonyms: MRN-interacting protein
• Gene Name: MRNIP
• Related Disease:
  Frontotemporal dementia and/or amyotrophic lateral sclerosis 3
  Paget disease of bone 3
• UniProt ID: MRNIP_HUMAN
• Pfam ID: PF15749
• Sequence:
  MASLQRSRVLRCCSCRLFQAHQVKKSVKWTCKACGEKQSFLQAYGEGSGADCRRHVQKLN
  LLQGQVSELPLRSLEETVSASEEENVGHQQAGNVKQQEKSQPSESRWLKYLEKDSQELEL
  EGTGVCFSKQPSSKMEEPGPRFSQDLPRKRKWSRSTVQPPCSRGVQDSGGSEVAWGPQKG
  QAGLTWKVKQGSSPCLQENSADCSAGELRGPGKELWSPIQQVTATSSKWAQFVLPPRKSS
  HVDSEQPRSLQRDPRPAGPAQAKQGTPRAQASREGLSRPTAAVQLPRATHPVTSGSERPC
  GKTSWDARTPWAEGGPLVLEAQNPRPTRLCDLFITGEDFDDDV
• Function: Plays a role in the cellular response to DNA damage and the maintenance of genome stability through its association with the MRN damage-sensing complex. Promotes chromatin loading and activity of the MRN complex to facilitate subsequent ATM-mediated DNA damage response signaling and DNA repair.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Frontotemporal dementia and/or amyotrophic lateral sclerosis 3	DISYMV4O	Strong	Genetic Variation	[1]
Paget disease of bone 3	DISZ9LUZ	Strong	CausalMutation	[2]

12 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of MRN complex-interacting protein (MRNIP).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of MRN complex-interacting protein (MRNIP).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of MRN complex-interacting protein (MRNIP).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of MRN complex-interacting protein (MRNIP).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of MRN complex-interacting protein (MRNIP).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of MRN complex-interacting protein (MRNIP).	[8]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of MRN complex-interacting protein (MRNIP).	[8]
Menadione	DMSJDTY	Approved	Menadione affects the expression of MRN complex-interacting protein (MRNIP).	[7]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of MRN complex-interacting protein (MRNIP).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of MRN complex-interacting protein (MRNIP).	[10]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of MRN complex-interacting protein (MRNIP).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of MRN complex-interacting protein (MRNIP).	[13]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of MRN complex-interacting protein (MRNIP).	[12]

References

• [1] Detection of SQSTM1/P392L post-zygotic mutations in Paget's disease of bone.Hum Genet. 2015 Jan;134(1):53-65. doi: 10.1007/s00439-014-1488-3. Epub 2014 Sep 21.
• [2] The Implications of the Sequestosome 1 Mutation P392L in Patients with Paget's Disease in a United States Cohort.Calcif Tissue Int. 2016 May;98(5):489-96. doi: 10.1007/s00223-015-0103-5. Epub 2015 Dec 28.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [5] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [8] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [11] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [12] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [13] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.