Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7PNO08)

• DOT Name: 5'-3' exoribonuclease 2
• Synonyms: EC 3.1.13.-; DHM1-like protein; DHP protein
• Gene Name: XRN2
• UniProt ID: XRN2_HUMAN
• EC Number: 3.1.13.-
• Pfam ID: PF17846 ; PF03159
• Sequence:
  MGVPAFFRWLSRKYPSIIVNCVEEKPKECNGVKIPVDASKPNPNDVEFDNLYLDMNGIIH
  PCTHPEDKPAPKNEDEMMVAIFEYIDRLFSIVRPRRLLYMAIDGVAPRAKMNQQRSRRFR
  ASKEGMEAAVEKQRVREEILAKGGFLPPEEIKERFDSNCITPGTEFMDNLAKCLRYYIAD
  RLNNDPGWKNLTVILSDASAPGEGEHKIMDYIRRQRAQPNHDPNTHHCLCGADADLIMLG
  LATHEPNFTIIREEFKPNKPKPCGLCNQFGHEVKDCEGLPREKKGKHDELADSLPCAEGE
  FIFLRLNVLREYLERELTMASLPFTFDVERSIDDWVFMCFFVGNDFLPHLPSLEIRENAI
  DRLVNIYKNVVHKTGGYLTESGYVNLQRVQMIMLAVGEVEDSIFKKRKDDEDSFRRRQKE
  KRKRMKRDQPAFTPSGILTPHALGSRNSPGSQVASNPRQAAYEMRMQNNSSPSISPNTSF
  TSDGSPSPLGGIKRKAEDSDSEPEPEDNVRLWEAGWKQRYYKNKFDVDAADEKFRRKVVQ
  SYVEGLCWVLRYYYQGCASWKWYYPFHYAPFASDFEGIADMPSDFEKGTKPFKPLEQLMG
  VFPAASGNFLPPSWRKLMSDPDSSIIDFYPEDFAIDLNGKKYAWQGVALLPFVDERRLRA
  ALEEVYPDLTPEETRRNSLGGDVLFVGKHHPLHDFILELYQTGSTEPVEVPPELCHGIQG
  KFSLDEEAILPDQIVCSPVPMLRDLTQNTVVSINFKDPQFAEDYIFKAVMLPGARKPAAV
  LKPSDWEKSSNGRQWKPQLGFNRDRRPVHLDQAAFRTLGHVMPRGSGTGIYSNAAPPPVT
  YQGNLYRPLLRGQAQIPKLMSNMRPQDSWRGPPPLFQQQRFDRGVGAEPLLPWNRMLQTQ
  NAAFQPNQYQMLAGPGGYPPRRDDRGGRQGYPREGRKYPLPPPSGRYNWN
• Function: Possesses 5'->3' exoribonuclease activity. May promote the termination of transcription by RNA polymerase II. During transcription termination, cleavage at the polyadenylation site liberates a 5' fragment which is subsequently processed to form the mature mRNA and a 3' fragment which remains attached to the elongating polymerase. The processive degradation of this 3' fragment by this protein may promote termination of transcription. Binds to RNA polymerase II (RNAp II) transcription termination R-loops formed by G-rich pause sites.
• Tissue Specificity: Expressed in the spleen, thymus, prostate, testis, ovary, small intestine, colon, peripheral blood leukocytes, heart, brain, placenta, lung, liver, skeletal muscle, kidney, and pancreas. Isoform 2 is expressed predominantly in peripheral blood leukocytes.
• KEGG Pathway:
  Ribosome biogenesis in eukaryotes (hsa03008)
  R. degradation (hsa03018)
• Reactome Pathway:
  Major pathway of rRNA processing in the nucleolus and cytosol (R-HSA-6791226)
  Association of TriC/CCT with target proteins during biosynthesis (R-HSA-390471)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of 5'-3' exoribonuclease 2.	[1]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 5'-3' exoribonuclease 2.	[2]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of 5'-3' exoribonuclease 2.	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of 5'-3' exoribonuclease 2.	[7]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of 5'-3' exoribonuclease 2.	[8]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of 5'-3' exoribonuclease 2.	[9]

4 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 5'-3' exoribonuclease 2.	[3]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of 5'-3' exoribonuclease 2.	[4]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of 5'-3' exoribonuclease 2.	[6]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of 5'-3' exoribonuclease 2.	[6]

References

• [1] 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.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [6] 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.
• [7] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [8] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [9] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.