Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNCF906)

• DOT Name: Exosome complex component RRP40 (EXOSC3)
• Synonyms: Exosome component 3; Ribosomal RNA-processing protein 40; p10
• Gene Name: EXOSC3
• Related Disease:
  Chronic renal failure
  End-stage renal disease
  Pontocerebellar hypoplasia type 1A
  Pontocerebellar hypoplasia type 1B
  Acute liver failure
  Acute myelogenous leukaemia
  Adult glioblastoma
  Central nervous system lymphoma
  Cerebral cavernous malformation
  Colitis
  Epilepsy
  Glioblastoma multiforme
  Glomerulonephritis
  Isolated congenital microcephaly
  Malabsorption syndrome
  Motor neurone disease
  Nervous system disease
  Paracoccidioidomycosis
  Pontocerebellar hypoplasia
  Respiratory disease
  Spinal muscular atrophy
  Varicose veins
  Meningioma
  Neoplasm
  Systemic lupus erythematosus
  Pontocerebellar hypoplasia type 1
  Complex hereditary spastic paraplegia
  Chronic kidney disease
  Neurodevelopmental disorder
  Osteoarthritis
  Systemic mycosis
• UniProt ID: EXOS3_HUMAN
• PDB ID: 2NN6; 6D6Q; 6D6R; 6H25
• Pfam ID: PF15985 ; PF21261 ; PF21262
• Sequence:
  MAEPASVAAESLAGSRARAARTVLGQVVLPGEELLLPEQEDAEGPGGAVERPLSLNARAC
  SRVRVVCGPGLRRCGDRLLVTKCGRLRHKEPGSGSGGGVYWVDSQQKRYVPVKGDHVIGI
  VTAKSGDIFKVDVGGSEPASLSYLSFEGATKRNRPNVQVGDLIYGQFVVANKDMEPEMVC
  IDSCGRANGMGVIGQDGLLFKVTLGLIRKLLAPDCEIIQEVGKLYPLEIVFGMNGRIWVK
  AKTIQQTLILANILEACEHMTSDQRKQIFSRLAES
• 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. EXOSC3 as peripheral part of the Exo-9 complex stabilizes the hexameric ring of RNase PH-domain subunits through contacts with EXOSC9 and EXOSC5.
• 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

31 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chronic renal failure	DISGG7K6	Definitive	Biomarker	[1]
End-stage renal disease	DISXA7GG	Definitive	Biomarker	[1]
Pontocerebellar hypoplasia type 1A	DIS7X0VS	Definitive	Autosomal recessive	[2]
Pontocerebellar hypoplasia type 1B	DISZO2HP	Definitive	Autosomal recessive	[3]
Acute liver failure	DIS5EZKX	Strong	Altered Expression	[4]
Acute myelogenous leukaemia	DISCSPTN	Strong	Genetic Variation	[5]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[6]
Central nervous system lymphoma	DISBYQTA	Strong	Biomarker	[7]
Cerebral cavernous malformation	DISLKNYA	Strong	Biomarker	[8]
Colitis	DISAF7DD	Strong	Genetic Variation	[9]
Epilepsy	DISBB28L	Strong	Genetic Variation	[10]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[7]
Glomerulonephritis	DISPZIQ3	Strong	Genetic Variation	[11]
Isolated congenital microcephaly	DISUXHZ6	Strong	Genetic Variation	[3]
Malabsorption syndrome	DISGMUVS	Strong	Biomarker	[12]
Motor neurone disease	DISUHWUI	Strong	Genetic Variation	[3]
Nervous system disease	DISJ7GGT	Strong	Genetic Variation	[13]
Paracoccidioidomycosis	DIS88F55	Strong	Biomarker	[14]
Pontocerebellar hypoplasia	DISRICMU	Strong	Biomarker	[15]
Respiratory disease	DISGGAGJ	Strong	Biomarker	[12]
Spinal muscular atrophy	DISTLKOB	Strong	Biomarker	[16]
Varicose veins	DISIMBN2	Strong	Biomarker	[17]
Meningioma	DISPT4TG	moderate	Altered Expression	[18]
Neoplasm	DISZKGEW	moderate	Altered Expression	[18]
Systemic lupus erythematosus	DISI1SZ7	moderate	Biomarker	[19]
Pontocerebellar hypoplasia type 1	DISU1PSQ	Supportive	Autosomal recessive	[3]
Complex hereditary spastic paraplegia	DIS9KXQY	Disputed	Genetic Variation	[20]
Chronic kidney disease	DISW82R7	Limited	Biomarker	[21]
Neurodevelopmental disorder	DIS372XH	Limited	Genetic Variation	[13]
Osteoarthritis	DIS05URM	Limited	Altered Expression	[22]
Systemic mycosis	DISYN1SP	Limited	Biomarker	[23]

11 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 Exosome complex component RRP40 (EXOSC3).	[24]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Exosome complex component RRP40 (EXOSC3).	[25]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Exosome complex component RRP40 (EXOSC3).	[26]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Exosome complex component RRP40 (EXOSC3).	[27]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Exosome complex component RRP40 (EXOSC3).	[24]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Exosome complex component RRP40 (EXOSC3).	[28]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Exosome complex component RRP40 (EXOSC3).	[29]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Exosome complex component RRP40 (EXOSC3).	[31]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Exosome complex component RRP40 (EXOSC3).	[32]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Exosome complex component RRP40 (EXOSC3).	[33]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Exosome complex component RRP40 (EXOSC3).	[34]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Exosome complex component RRP40 (EXOSC3).	[30]

References

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