General Information of Drug Off-Target (DOT) (ID: OTB1QQJJ)

DOT Name Exosome complex component CSL4 (EXOSC1)
Synonyms Exosome component 1
Gene Name EXOSC1
Related Disease
Inflammatory bowel disease ( )
Lyme disease ( )
Pontocerebellar hypoplasia, type 1F ( )
Rheumatoid arthritis ( )
UniProt ID
EXOS1_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
2NN6; 6D6Q; 6D6R; 6H25
Pfam ID
PF14382 ; PF10447
Sequence
MAPPVRYCIPGERLCNLEEGSPGSGTYTRHGYIFSSLAGCLMKSSENGALPVVSVVRETE
SQLLPDVGAIVTCKVSSINSRFAKVHILYVGSMPLKNSFRGTIRKEDVRATEKDKVEIYK
SFRPGDIVLAKVISLGDAQSNYLLTTAENELGVVVAHSESGIQMVPISWCEMQCPKTHTK
EFRKVARVQPEFLQT
Function
Non-catalytic component of the RNA exosome complex which has 3'->5' exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events. In the nucleus, the RNA exosome complex is involved in proper maturation of stable RNA species such as rRNA, snRNA and snoRNA, in the elimination of RNA processing by-products and non-coding 'pervasive' transcripts, such as antisense RNA species and promoter-upstream transcripts (PROMPTs), and of mRNAs with processing defects, thereby limiting or excluding their export to the cytoplasm. The RNA exosome may be involved in Ig class switch recombination (CSR) and/or Ig variable region somatic hypermutation (SHM) by targeting AICDA deamination activity to transcribed dsDNA substrates. In the cytoplasm, the RNA exosome complex is involved in general mRNA turnover and specifically degrades inherently unstable mRNAs containing AU-rich elements (AREs) within their 3' untranslated regions, and in RNA surveillance pathways, preventing translation of aberrant mRNAs. It seems to be involved in degradation of histone mRNA. The catalytic inactive RNA exosome core complex of 9 subunits (Exo-9) is proposed to play a pivotal role in the binding and presentation of RNA for ribonucleolysis, and to serve as a scaffold for the association with catalytic subunits and accessory proteins or complexes. EXOSC1 as peripheral part of the Exo-9 complex stabilizes the hexameric ring of RNase PH-domain subunits through contacts with EXOSC6 and EXOSC8.
KEGG Pathway
R. degradation (hsa03018 )
Reactome Pathway
mRNA decay by 3' to 5' exoribonuclease (R-HSA-429958 )
Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA (R-HSA-450385 )
Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA (R-HSA-450513 )
KSRP (KHSRP) binds and destabilizes mRNA (R-HSA-450604 )
Major pathway of rRNA processing in the nucleolus and cytosol (R-HSA-6791226 )
ATF4 activates genes in response to endoplasmic reticulum stress (R-HSA-380994 )

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Inflammatory bowel disease DISGN23E Strong Biomarker [1]
Lyme disease DISO70G5 Strong Biomarker [2]
Pontocerebellar hypoplasia, type 1F DISUBUVD Limited Autosomal recessive [3]
Rheumatoid arthritis DISTSB4J Limited Genetic Variation [4]
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Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
3 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate increases the expression of Exosome complex component CSL4 (EXOSC1). [5]
Ciclosporin DMAZJFX Approved Ciclosporin increases the expression of Exosome complex component CSL4 (EXOSC1). [6]
Ivermectin DMDBX5F Approved Ivermectin decreases the expression of Exosome complex component CSL4 (EXOSC1). [7]
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1 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Coumarin DM0N8ZM Investigative Coumarin increases the phosphorylation of Exosome complex component CSL4 (EXOSC1). [8]
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References

1 Bioinformatics analysis reveals transcriptome and microRNA signatures and drug repositioning targets for IBD and other autoimmune diseases.Inflamm Bowel Dis. 2012 Dec;18(12):2315-33. doi: 10.1002/ibd.22958. Epub 2012 Apr 5.
2 Molecular analysis of the channel-forming protein P13 and its paralogue family 48 from different Lyme disease Borrelia species.Microbiology (Reading). 2004 Mar;150(Pt 3):549-559. doi: 10.1099/mic.0.26728-0.
3 Bi-allelic missense variant, p.Ser35Leu in EXOSC1 is associated with pontocerebellar hypoplasia. Clin Genet. 2021 Apr;99(4):594-600. doi: 10.1111/cge.13928. Epub 2021 Jan 28.
4 High-specificity bioinformatics framework for epigenomic profiling of discordant twins reveals specific and shared markers for ACPA and ACPA-positive rheumatoid arthritis.Genome Med. 2016 Nov 22;8(1):124. doi: 10.1186/s13073-016-0374-0.
5 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.
6 Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
7 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.
8 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.