Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7UPHJS)

• DOT Name: Exosome complex exonuclease RRP44 (DIS3)
• Synonyms: EC 3.1.13.-; EC 3.1.26.-; Protein DIS3 homolog; Ribosomal RNA-processing protein 44
• Gene Name: DIS3
• Related Disease:
  Adenoma
  Advanced cancer
  Carcinoma
  Chromosomal disorder
  Colorectal carcinoma
  Perlman syndrome
  Plasma cell myeloma
  Neoplasm
• UniProt ID: RRP44_HUMAN
• PDB ID: 6D6Q; 6D6R; 6H25
• EC Number: 3.1.13.-; 3.1.26.-
• Pfam ID: PF17849 ; PF13638 ; PF00773 ; PF17216 ; PF17215
• Sequence:
  MLKSKTFLKKTRAGGVMKIVREHYLRDDIGCGAPGCAACGGAHEGPALEPQPQDPASSVC
  PQPHYLLPDTNVLLHQIDVLEDPAIRNVIVLQTVLQEVRNRSAPVYKRIRDVTNNQEKHF
  YTFTNEHHRETYVEQEQGENANDRNDRAIRVAAKWYNEHLKKMSADNQLQVIFITNDRRN
  KEKAIEEGIPAFTCEEYVKSLTANPELIDRLACLSEEGNEIESGKIIFSEHLPLSKLQQG
  IKSGTYLQGTFRASRENYLEATVWIHGDNEENKEIILQGLKHLNRAVHEDIVAVELLPKS
  QWVAPSSVVLHDEGQNEEDVEKEEETERMLKTAVSEKMLKPTGRVVGIIKRNWRPYCGML
  SKSDIKESRRHLFTPADKRIPRIRIETRQASTLEGRRIIVAIDGWPRNSRYPNGHFVRNL
  GDVGEKETETEVLLLEHDVPHQPFSQAVLSFLPKMPWSITEKDMKNREDLRHLCICSVDP
  PGCTDIDDALHCRELENGNLEVGVHIADVSHFIRPGNALDQESARRGTTVYLCEKRIDMV
  PELLSSNLCSLKCDVDRLAFSCIWEMNHNAEILKTKFTKSVINSKASLTYAEAQLRIDSA
  NMNDDITTSLRGLNKLAKILKKRRIEKGALTLSSPEVRFHMDSETHDPIDLQTKELRETN
  SMVEEFMLLANISVAKKIHEEFSEHALLRKHPAPPPSNYEILVKAARSRNLEIKTDTAKS
  LAESLDQAESPTFPYLNTLLRILATRCMMQAVYFCSGMDNDFHHYGLASPIYTHFTSPIR
  RYADVIVHRLLAVAIGADCTYPELTDKHKLADICKNLNFRHKMAQYAQRASVAFHTQLFF
  KSKGIVSEEAYILFVRKNAIVVLIPKYGLEGTVFFEEKDKPNPQLIYDDEIPSLKIEDTV
  FHVFDKVKVKIMLDSSNLQHQKIRMSLVEPQIPGISIPTDTSNMDLNGPKKKKMKLGK
• Function: Putative 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. DIS3 has both 3'-5' exonuclease and endonuclease activities.
• Tissue Specificity: Widely expressed.
• 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

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenoma	DIS78ZEV	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[2]
Carcinoma	DISH9F1N	Strong	Altered Expression	[1]
Chromosomal disorder	DISM5BB5	Strong	Genetic Variation	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[1]
Perlman syndrome	DISN3KMO	Strong	Genetic Variation	[4]
Plasma cell myeloma	DIS0DFZ0	Strong	Genetic Variation	[5]
Neoplasm	DISZKGEW	Limited	Genetic Variation	[6]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitoxantrone	DMM39BF	Approved	Exosome complex exonuclease RRP44 (DIS3) affects the response to substance of Mitoxantrone.	[13]

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 Exosome complex exonuclease RRP44 (DIS3).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Exosome complex exonuclease RRP44 (DIS3).	[8]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Exosome complex exonuclease RRP44 (DIS3).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Exosome complex exonuclease RRP44 (DIS3).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Exosome complex exonuclease RRP44 (DIS3).	[12]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 affects the binding of Exosome complex exonuclease RRP44 (DIS3).	[10]

References

• [1] Gene-dosage dependent overexpression at the 13q amplicon identifies DIS3 as candidate oncogene in colorectal cancer progression.Genes Chromosomes Cancer. 2014 Apr;53(4):339-48. doi: 10.1002/gcc.22144. Epub 2014 Jan 29.
• [2] DIS3 isoforms vary in their endoribonuclease activity and are differentially expressed within haematological cancers.Biochem J. 2018 Jun 29;475(12):2091-2105. doi: 10.1042/BCJ20170962.
• [3] Global methylation patterns in primary plasma cell leukemia.Leuk Res. 2018 Oct;73:95-102. doi: 10.1016/j.leukres.2018.09.007. Epub 2018 Sep 18.
• [4] Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility. Nat Genet. 2012 Feb 5;44(3):277-84. doi: 10.1038/ng.1071.
• [5] The RNA Exosome and Human Disease.Methods Mol Biol. 2020;2062:3-33. doi: 10.1007/978-1-4939-9822-7_1.
• [6] The molecular spectrum and clinical impact of DIS3 mutations in multiple myeloma.Br J Haematol. 2015 Apr;169(1):57-70. doi: 10.1111/bjh.13256. Epub 2014 Dec 17.
• [7] 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.
• [8] 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.
• [9] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [10] "Minimalist" cyclopropene-containing photo-cross-linkers suitable for live-cell imaging and affinity-based protein labeling. J Am Chem Soc. 2014 Jul 16;136(28):9990-8. doi: 10.1021/ja502780z. Epub 2014 Jul 3.
• [11] 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.
• [12] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [13] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.