Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7O00YX)

• DOT Name: RNA 3'-terminal phosphate cyclase-like protein (RCL1)
• Gene Name: RCL1
• Related Disease:
  Crohn disease
  Dengue
  Depression
  Lung adenocarcinoma
  Acute myelogenous leukaemia
• UniProt ID: RCL1_HUMAN
• PDB ID: 7MQ8; 7MQ9; 7MQA
• Pfam ID: PF01137 ; PF05189
• Sequence:
  MATQAHSLSYAGCNFLRQRLVLSTLSGRPVKIRKIRARDDNPGLRDFEASFIRLLDKITN
  GSRIEINQTGTTLYYQPGLLYGGSVEHDCSVLRGIGYYLESLLCLAPFMKHPLKIVLRGV
  TNDQVDPSVDVLKATALPLLKQFGIDGESFELKIVRRGMPPGGGGEVVFSCPVRKVLKPI
  QLTDPGKIKRIRGMAYSVRVSPQMANRIVDSARSILNKFIPDIYIYTDHMKGVNSGKSPG
  FGLSLVAETTSGTFLSAELASNPQGQGAAVLPEDLGRNCARLLLEEIYRGGCVDSTNQSL
  ALLLMTLGQQDVSKVLLGPLSPYTIEFLRHLKSFFQIMFKIETKPCGEELKGGDKVLMTC
  VGIGFSNLSKTLK
• Function: Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome. Does not have cyclase activity.
• KEGG Pathway: Ribosome biogenesis in eukaryotes (hsa03008)
• Reactome Pathway:
  Major pathway of rRNA processing in the nucleolus and cytosol (R-HSA-6791226)
  rRNA modification in the nucleus and cytosol (R-HSA-6790901)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Crohn disease	DIS2C5Q8	Strong	Biomarker	[1]
Dengue	DISKH221	Strong	Genetic Variation	[2]
Depression	DIS3XJ69	Strong	Biomarker	[3]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[4]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of RNA 3'-terminal phosphate cyclase-like protein (RCL1).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of RNA 3'-terminal phosphate cyclase-like protein (RCL1).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of RNA 3'-terminal phosphate cyclase-like protein (RCL1).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of RNA 3'-terminal phosphate cyclase-like protein (RCL1).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of RNA 3'-terminal phosphate cyclase-like protein (RCL1).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of RNA 3'-terminal phosphate cyclase-like protein (RCL1).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of RNA 3'-terminal phosphate cyclase-like protein (RCL1).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of RNA 3'-terminal phosphate cyclase-like protein (RCL1).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of RNA 3'-terminal phosphate cyclase-like protein (RCL1).	[14]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of RNA 3'-terminal phosphate cyclase-like protein (RCL1).	[15]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of RNA 3'-terminal phosphate cyclase-like protein (RCL1).	[16]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of RNA 3'-terminal phosphate cyclase-like protein (RCL1).	[11]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of RNA 3'-terminal phosphate cyclase-like protein (RCL1).	[11]
Estrone	DM5T6US	Approved	Estrone increases the expression of RNA 3'-terminal phosphate cyclase-like protein (RCL1).	[11]
Mestranol	DMG3F94	Approved	Mestranol increases the expression of RNA 3'-terminal phosphate cyclase-like protein (RCL1).	[11]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of RNA 3'-terminal phosphate cyclase-like protein (RCL1).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of RNA 3'-terminal phosphate cyclase-like protein (RCL1).	[17]
HEXESTROL	DM9AGWQ	Withdrawn from market	HEXESTROL increases the expression of RNA 3'-terminal phosphate cyclase-like protein (RCL1).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of RNA 3'-terminal phosphate cyclase-like protein (RCL1).	[18]

References

• [1] Neutrophil GM-CSF signaling in inflammatory bowel disease patients is influenced by non-coding genetic variants.Sci Rep. 2019 Jun 24;9(1):9168. doi: 10.1038/s41598-019-45701-2.
• [2] Association of BAK1 single nucleotide polymorphism with a risk for dengue hemorrhagic fever.BMC Med Genet. 2016 Jul 11;17(1):43. doi: 10.1186/s12881-016-0305-3.
• [3] A rare missense variant in RCL1 segregates with depression in extended families.Mol Psychiatry. 2018 May;23(5):1120-1126. doi: 10.1038/mp.2017.49. Epub 2017 Mar 21.
• [4] c-Myc targeted regulators of cell metabolism in a transgenic mouse model of papillary lung adenocarcinoma.Oncotarget. 2016 Oct 4;7(40):65514-65539. doi: 10.18632/oncotarget.11804.
• [5] 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.
• [6] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Moving toward integrating gene expression profiling into high-throughput testing: a gene expression biomarker accurately predicts estrogen receptor alpha modulation in a microarray compendium. Toxicol Sci. 2016 May;151(1):88-103.
• [12] 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.
• [13] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [14] Endoplasmic reticulum stress contributes to arsenic trioxide-induced intrinsic apoptosis in human umbilical and bone marrow mesenchymal stem cells. Environ Toxicol. 2016 Mar;31(3):314-28.
• [15] 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.
• [16] 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.
• [17] Gene expression changes associated with altered growth and differentiation in benzo[a]pyrene or arsenic exposed normal human epidermal keratinocytes. J Appl Toxicol. 2008 May;28(4):491-508.
• [18] Evaluation of estrogen receptor alpha activation by glyphosate-based herbicide constituents. Food Chem Toxicol. 2017 Oct;108(Pt A):30-42.