Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSHNJ6B)

• DOT Name: Phosphorylated adapter RNA export protein (PHAX)
• Synonyms: RNA U small nuclear RNA export adapter protein
• Gene Name: PHAX
• Related Disease:
  Zika virus infection
  Isolated Pierre-Robin syndrome
  Acute myelogenous leukaemia
• UniProt ID: PHAX_HUMAN
• PDB ID: 2XC7
• Pfam ID: PF10258
• Sequence:
  MALEVGDMEDGQLSDSDSDMTVAPSDRPLQLPKVLGGDSAMRAFQNTATACAPVSHYRAV
  ESVDSSEESFSDSDDDSCLWKRKRQKCFNPPPKPEPFQFGQSSQKPPVAGGKKINNIWGA
  VLQEQNQDAVATELGILGMEGTIDRSRQSETYNYLLAKKLRKESQEHTKDLDKELDEYMH
  GGKKMGSKEEENGQGHLKRKRPVKDRLGNRPEMNYKGRYEITAEDSQEKVADEISFRLQE
  PKKDLIARVVRIIGNKKAIELLMETAEVEQNGGLFIMNGSRRRTPGGVFLNLLKNTPSIS
  EEQIKDIFYIENQKEYENKKAARKRRTQVLGKKMKQAIKSLNFQEDDDTSRETFASDTNE
  ALASLDESQEGHAEAKLEAEEAIEVDHSHDLDIF
• Function: A phosphoprotein adapter involved in the XPO1-mediated U snRNA export from the nucleus. Bridge components required for U snRNA export, the cap binding complex (CBC)-bound snRNA on the one hand and the GTPase Ran in its active GTP-bound form together with the export receptor XPO1 on the other. Its phosphorylation in the nucleus is required for U snRNA export complex assembly and export, while its dephosphorylation in the cytoplasm causes export complex disassembly. It is recycled back to the nucleus via the importin alpha/beta heterodimeric import receptor. The directionality of nuclear export is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus. Its compartmentalized phosphorylation cycle may also contribute to the directionality of export. Binds strongly to m7G-capped U1 and U5 small nuclear RNAs (snRNAs) in a sequence-unspecific manner and phosphorylation-independent manner. Also plays a role in the biogenesis of U3 small nucleolar RNA (snoRNA). Involved in the U3 snoRNA transport from nucleoplasm to Cajal bodies. Binds strongly to m7G-capped U3, U8 and U13 precursor snoRNAs and weakly to trimethylated (TMG)-capped U3, U8 and U13 snoRNAs. Binds also to telomerase RNA.
• KEGG Pathway: Nucleocytoplasmic transport (hsa03013)
• Reactome Pathway:
  RNA polymerase II transcribes snRNA genes (R-HSA-6807505)
  snRNP Assembly (R-HSA-191859)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Zika virus infection	DISQUCTY	Strong	Biomarker	[1]
Isolated Pierre-Robin syndrome	DISVEHG7	Disputed	Genetic Variation	[2]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Phosphorylated adapter RNA export protein (PHAX).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate affects the expression of Phosphorylated adapter RNA export protein (PHAX).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Phosphorylated adapter RNA export protein (PHAX).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Phosphorylated adapter RNA export protein (PHAX).	[8]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Phosphorylated adapter RNA export protein (PHAX).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of Phosphorylated adapter RNA export protein (PHAX).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Phosphorylated adapter RNA export protein (PHAX).	[10]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Phosphorylated adapter RNA export protein (PHAX).	[11]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Phosphorylated adapter RNA export protein (PHAX).	[7]

References

• [1] Zika virus noncoding sfRNAs sequester multiple host-derived RNA-binding proteins and modulate mRNA decay and splicing during infection.J Biol Chem. 2019 Nov 1;294(44):16282-16296. doi: 10.1074/jbc.RA119.009129. Epub 2019 Sep 13.
• [2] A syndromic form of Pierre Robin sequence is caused by 5q23 deletions encompassing FBN2 and PHAX.Eur J Med Genet. 2014 Oct;57(10):587-95. doi: 10.1016/j.ejmg.2014.08.007. Epub 2014 Sep 3.
• [3] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [7] 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.
• [8] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [9] 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.
• [10] 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.
• [11] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.