Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSQY30V)

• DOT Name: Exosome RNA helicase MTR4 (MTREX)
• Synonyms: EC 3.6.4.13; ATP-dependent RNA helicase DOB1; ATP-dependent RNA helicase SKIV2L2; Superkiller viralicidic activity 2-like 2; TRAMP-like complex helicase
• Gene Name: MTREX
• Related Disease:
  Cervical carcinoma
  Cervical Intraepithelial neoplasia
  Dysplasia of cervix
  Human papillomavirus infection
  Systemic lupus erythematosus
• UniProt ID: MTREX_HUMAN
• PDB ID: 6C90; 6D6Q; 6D6R; 6IEG; 6IEH; 6RO1; 7S7B; 7S7C; 7Z4Y; 7Z4Z; 7Z52
• EC Number: 3.6.4.13
• Pfam ID: PF00270 ; PF08148 ; PF00271 ; PF21408 ; PF13234
• Sequence:
  MADAFGDELFSVFEGDSTTAAGTKKDKEKDKGKWKGPPGSADKAGKRFDGKLQSESTNNG
  KNKRDVDFEGTDEPIFGKKPRIEESITEDLSLADLMPRVKVQSVETVEGCTHEVALPAEE
  DYLPLKPRVGKAAKEYPFILDAFQREAIQCVDNNQSVLVSAHTSAGKTVCAEYAIALALR
  EKQRVIFTSPIKALSNQKYREMYEEFQDVGLMTGDVTINPTASCLVMTTEILRSMLYRGS
  EVMREVAWVIFDEIHYMRDSERGVVWEETIILLPDNVHYVFLSATIPNARQFAEWICHLH
  KQPCHVIYTDYRPTPLQHYIFPAGGDGLHLVVDENGDFREDNFNTAMQVLRDAGDLAKGD
  QKGRKGGTKGPSNVFKIVKMIMERNFQPVIIFSFSKKDCEAYALQMTKLDFNTDEEKKMV
  EEVFSNAIDCLSDEDKKLPQVEHVLPLLKRGIGIHHGGLLPILKETIEILFSEGLIKALF
  ATETFAMGINMPARTVLFTNARKFDGKDFRWISSGEYIQMSGRAGRRGMDDRGIVILMVD
  EKMSPTIGKQLLKGSADPLNSAFHLTYNMVLNLLRVEEINPEYMLEKSFYQFQHYRAIPG
  VVEKVKNSEEQYNKIVIPNEESVVIYYKIRQQLAKLGKEIEEYIHKPKYCLPFLQPGRLV
  KVKNEGDDFGWGVVVNFSKKSNVKPNSGELDPLYVVEVLLRCSKESLKNSATEAAKPAKP
  DEKGEMQVVPVLVHLLSAISSVRLYIPKDLRPVDNRQSVLKSIQEVQKRFPDGIPLLDPI
  DDMGIQDQGLKKVIQKVEAFEHRMYSHPLHNDPNLETVYTLCEKKAQIAIDIKSAKRELK
  KARTVLQMDELKCRKRVLRRLGFATSSDVIEMKGRVACEISSADELLLTEMMFNGLFNDL
  SAEQATALLSCFVFQENSSEMPKLTEQLAGPLRQMQECAKRIAKVSAEAKLEIDEETYLS
  SFKPHLMDVVYTWATGATFAHICKMTDVFEGSIIRCMRRLEELLRQMCQAAKAIGNTELE
  NKFAEGITKIKRDIVFAASLYL
• Function: Catalyzes the ATP-dependent unwinding of RNA duplexes with a single-stranded 3' RNA extension. Central subunit of many protein complexes, namely TRAMP-like, nuclear exosome targeting (NEXT) and poly(A) tail exosome targeting (PAXT). NEXT functions as an RNA exosome cofactor that directs a subset of non-coding short-lived RNAs for exosomal degradation. NEXT is involved in surveillance and turnover of aberrant transcripts and non-coding RNAs. PAXT directs a subset of long and polyadenylated poly(A) RNAs for exosomal degradation. The RNA exosome is fundamental for the degradation of RNA in eukaryotic nuclei. Substrate targeting is facilitated by its cofactor ZCCHC8, which links to RNA-binding protein adapters. Associated with the RNA exosome complex and involved in the 3'-processing of the 7S pre-RNA to the mature 5.8S rRNA. May be involved in pre-mRNA splicing. In the context of NEXT complex can also in vitro unwind DNA:RNA heteroduplexes with a 3' poly (A) RNA tracking strand. Can promote unwinding and degradation of structured RNA substrates when associated with the nuclear exosome and its cofactors. Can displace a DNA strand while translocating on RNA to ultimately degrade the RNA within a DNA/RNA heteroduplex. Plays a role in DNA damage response.
• KEGG Pathway: R. degradation (hsa03018)
• Reactome Pathway:
  mRNA Splicing - Major Pathway (R-HSA-72163)
  Major pathway of rRNA processing in the nucleolus and cytosol (R-HSA-6791226)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cervical carcinoma	DIST4S00	Strong	Genetic Variation	[1]
Cervical Intraepithelial neoplasia	DISXP757	Strong	Genetic Variation	[1]
Dysplasia of cervix	DISOAROS	Strong	Genetic Variation	[1]
Human papillomavirus infection	DISX61LX	Strong	Genetic Variation	[1]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[2]

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 RNA helicase MTR4 (MTREX).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Exosome RNA helicase MTR4 (MTREX).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Exosome RNA helicase MTR4 (MTREX).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Exosome RNA helicase MTR4 (MTREX).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Exosome RNA helicase MTR4 (MTREX).	[7]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol increases the expression of Exosome RNA helicase MTR4 (MTREX).	[8]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Exosome RNA helicase MTR4 (MTREX).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Exosome RNA helicase MTR4 (MTREX).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Exosome RNA helicase MTR4 (MTREX).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Exosome RNA helicase MTR4 (MTREX).	[13]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Exosome RNA helicase MTR4 (MTREX).	[14]

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 RNA helicase MTR4 (MTREX).	[10]

References

• [1] HLA DOA1 and DOB1 loci in Honduran women with cervical dysplasia and invasive cervical carcinoma and their relationship to human papillomavirus infection.Hum Biol. 1999 Jun;71(3):367-79.
• [2] Polymorphism of the DQA1 promoter region (QAP) and DRB1, QAP, DQA1, DQB1 haplotypes in systemic lupus erythematosus. SLE Study Group members.Immunogenetics. 1993;38(6):421-9. doi: 10.1007/BF00184522.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [5] 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.
• [6] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [7] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [8] The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
• [9] The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
• [10] 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.
• [11] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [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] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.