Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTE7W7Y5)

• DOT Name: Proline-rich nuclear receptor coactivator 2 (PNRC2)
• Gene Name: PNRC2
• Related Disease:
  Clear cell renal carcinoma
  Renal cell carcinoma
• UniProt ID: PNRC2_HUMAN
• PDB ID: 4B6H; 5KQ1; 5KQ4
• Pfam ID: PF15365
• Sequence:
  MGGGERYNIPAPQSRNVSKNQQQLNRQKTKEQNSQMKIVHKKKERGHGYNSSAAAWQAMQ
  NGGKNKNFPNNQSWNSSLSGPRLLFKSQANQNYAGAKFSEPPSPSVLPKPPSHWVPVSFN
  PSDKEIMTFQLKTLLKVQV
• Function: Involved in nonsense-mediated mRNA decay (NMD) by acting as a bridge between the mRNA decapping complex and the NMD machinery. May act by targeting the NMD machinery to the P-body and recruiting the decapping machinery to aberrant mRNAs. Required for UPF1/RENT1 localization to the P-body. Plays a role in glucocorticoid receptor-mediated mRNA degradation by interacting with the glucocorticoid receptor NR3C1 in a ligand-dependent manner when it is bound to the 5' UTR of target mRNAs and recruiting the RNA helicase UPF1 and the mRNA-decapping enzyme DCP1A, leading to RNA decay. Also acts as a nuclear receptor coactivator. May play a role in controlling the energy balance between energy storage and energy expenditure.
• Tissue Specificity: Expressed in heart, lung, muscle and brain.
• Reactome Pathway: Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) (R-HSA-975957)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Clear cell renal carcinoma	DISBXRFJ	Limited	Biomarker	[1]
Renal cell carcinoma	DISQZ2X8	Limited	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Proline-rich nuclear receptor coactivator 2 (PNRC2).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Proline-rich nuclear receptor coactivator 2 (PNRC2).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Proline-rich nuclear receptor coactivator 2 (PNRC2).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Proline-rich nuclear receptor coactivator 2 (PNRC2).	[5]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Proline-rich nuclear receptor coactivator 2 (PNRC2).	[6]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Proline-rich nuclear receptor coactivator 2 (PNRC2).	[7]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Proline-rich nuclear receptor coactivator 2 (PNRC2).	[8]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Proline-rich nuclear receptor coactivator 2 (PNRC2).	[10]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Proline-rich nuclear receptor coactivator 2 (PNRC2).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Proline-rich nuclear receptor coactivator 2 (PNRC2).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Proline-rich nuclear receptor coactivator 2 (PNRC2).	[11]

References

• [1] MiR-23a-3p acts as an oncogene and potential prognostic biomarker by targeting PNRC2 in RCC.Biomed Pharmacother. 2019 Feb;110:656-666. doi: 10.1016/j.biopha.2018.11.065. Epub 2018 Dec 12.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [7] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [8] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [9] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [10] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [11] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [12] In vitro effects of aldehydes present in tobacco smoke on gene expression in human lung alveolar epithelial cells. Toxicol In Vitro. 2013 Apr;27(3):1072-81.