Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF6DCYB)

• DOT Name: Activating signal cointegrator 1 complex subunit 3 (ASCC3)
• Synonyms: EC 3.6.4.12; ASC-1 complex subunit p200; ASC1p200; Helicase, ATP binding 1; Trip4 complex subunit p200
• Gene Name: ASCC3
• Related Disease:
  Advanced cancer
  Neoplasm of testis
  Chronic hepatitis B virus infection
  Hepatitis B virus infection
  Intellectual disability
• UniProt ID: ASCC3_HUMAN
• PDB ID: 6YXQ; 8ALZ
• EC Number: 3.6.4.12
• Pfam ID: PF00270 ; PF00271 ; PF02889
• Sequence:
  MALPRLTGALRSFSNVTKQDNYNEEVADLKIKRSKLHEQVLDLGLTWKKIIKFLNEKLEK
  SKMQSINEDLKDILHAAKQIVGTDNGREAIESGAAFLFMTFHLKDSVGHKETKAIKQMFG
  PFPSSSATAACNATNRIISHFSQDDLTALVQMTEKEHGDRVFFGKNLAFSFDMHDLDHFD
  ELPINGETQKTISLDYKKFLNEHLQEACTPELKPVEKTNGSFLWCEVEKYLNSTLKEMTE
  VPRVEDLCCTLYDMLASIKSGDELQDELFELLGPEGLELIEKLLQNRITIVDRFLNSSND
  HRFQALQDNCKKILGENAKPNYGCQVTIQSEQEKQLMKQYRREEKRIARREKKAGEDLEV
  SEGLMCFDPKELRIQREQALLNARSVPILSRQRDADVEKIHYPHVYDSQAEAMKTSAFIA
  GAKMILPEGIQRENNKLYEEVRIPYSEPMPLSFEEKPVYIQDLDEIGQLAFKGMKRLNRI
  QSIVFETAYNTNENMLICAPTGAGKTNIAMLTVLHEIRQHFQQGVIKKNEFKIVYVAPMK
  ALAAEMTDYFSRRLEPLGIIVKELTGDMQLSKSEILRTQMLVTTPEKWDVVTRKSVGDVA
  LSQIVRLLILDEVHLLHEDRGPVLESIVARTLRQVESTQSMIRILGLSATLPNYLDVATF
  LHVNPYIGLFFFDGRFRPVPLGQTFLGIKCANKMQQLNNMDEVCYENVLKQVKAGHQVMV
  FVHARNATVRTAMSLIERAKNCGHIPFFFPTQGHDYVLAEKQVQRSRNKQVRELFPDGFS
  IHHAGMLRQDRNLVENLFSNGHIKVLVCTATLAWGVNLPAHAVIIKGTQIYAAKRGSFVD
  LGILDVMQIFGRAGRPQFDKFGEGIIITTHDKLSHYLTLLTQRNPIESQFLESLADNLNA
  EIALGTVTNVEEAVKWISYTYLYVRMRANPLAYGISHKAYQIDPTLRKHREQLVIEVGRK
  LDKAQMIRFEERTGYFSSTDLGRTASHYYIKYNTIETFNELFDAHKTEGDIFAIVSKAEE
  FDQIKVREEEIEELDTLLSNFCELSTPGGVENSYGKINILLQTYISRGEMDSFSLISDSA
  YVAQNAARIVRALFEIALRKRWPTMTYRLLNLSKVIDKRLWGWASPLRQFSILPPHILTR
  LEEKKLTVDKLKDMRKDEIGHILHHVNIGLKVKQCVHQIPSVMMEASIQPITRTVLRVTL
  SIYADFTWNDQVHGTVGEPWWIWVEDPTNDHIYHSEYFLALKKQVISKEAQLLVFTIPIF
  EPLPSQYYIRAVSDRWLGAEAVCIINFQHLILPERHPPHTELLDLQPLPITALGCKAYEA
  LYNFSHFNPVQTQIFHTLYHTDCNVLLGAPTGSGKTVAAELAIFRVFNKYPTSKAVYIAP
  LKALVRERMDDWKVRIEEKLGKKVIELTGDVTPDMKSIAKADLIVTTPEKWDGVSRSWQN
  RNYVQQVTILIIDEIHLLGEERGPVLEVIVSRTNFISSHTEKPVRIVGLSTALANARDLA
  DWLNIKQMGLFNFRPSVRPVPLEVHIQGFPGQHYCPRMASMNKPAFQAIRSHSPAKPVLI
  FVSSRRQTRLTALELIAFLATEEDPKQWLNMDEREMENIIATVRDSNLKLTLAFGIGMHH
  AGLHERDRKTVEELFVNCKVQVLIATSTLAWGVNFPAHLVIIKGTEYYDGKTRRYVDFPI
  TDVLQMMGRAGRPQFDDQGKAVILVHDIKKDFYKKFLYEPFPVESSLLGVLSDHLNAEIA
  GGTITSKQDALDYITWTYFFRRLIMNPSYYNLGDVSHDSVNKFLSHLIEKSLIELELSYC
  IEIGEDNRSIEPLTYGRIASYYYLKHQTVKMFKDRLKPECSTEELLSILSDAEEYTDLPV
  RHNEDHMNSELAKCLPIESNPHSFDSPHTKAHLLLQAHLSRAMLPCPDYDTDTKTVLDQA
  LRVCQAMLDVAANQGWLVTVLNITNLIQMVIQGRWLKDSSLLTLPNIENHHLHLFKKWKP
  IMKGPHARGRTSIESLPELIHACGGKDHVFSSMVESELHAAKTKQAWNFLSHLPVINVGI
  SVKGSWDDLVEGHNELSVSTLTADKRDDNKWIKLHADQEYVLQVSLQRVHFGFHKGKPES
  CAVTPRFPKSKDEGWFLILGEVDKRELIALKRVGYIRNHHVASLSFYTPEIPGRYIYTLY
  FMSDCYLGLDQQYDIYLNVTQASLSAQVNTKVSDSLTDLALK
• Function: ATPase involved both in DNA repair and rescue of stalled ribosomes. 3'-5' DNA helicase involved in repair of alkylated DNA: promotes DNA unwinding to generate single-stranded substrate needed for ALKBH3, enabling ALKBH3 to process alkylated N3-methylcytosine (3mC) within double-stranded regions. Also involved in activation of the ribosome quality control (RQC) pathway, a pathway that degrades nascent peptide chains during problematic translation. Drives the splitting of stalled ribosomes that are ubiquitinated in a ZNF598-dependent manner, as part of the ribosome quality control trigger (RQT) complex. Part of the ASC-1 complex that enhances NF-kappa-B, SRF and AP1 transactivation.
• Tissue Specificity: Ubiquitous.
• Reactome Pathway: ALKBH3 mediated reversal of alkylation damage (R-HSA-112126)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Neoplasm of testis	DISK4XHT	Strong	Biomarker	[2]
Chronic hepatitis B virus infection	DISHL4NT	Limited	Genetic Variation	[3]
Hepatitis B virus infection	DISLQ2XY	Limited	Genetic Variation	[3]
Intellectual disability	DISMBNXP	Limited	Autosomal recessive	[4]

2 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 Activating signal cointegrator 1 complex subunit 3 (ASCC3).	[5]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Activating signal cointegrator 1 complex subunit 3 (ASCC3).	[11]

14 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 Activating signal cointegrator 1 complex subunit 3 (ASCC3).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Activating signal cointegrator 1 complex subunit 3 (ASCC3).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Activating signal cointegrator 1 complex subunit 3 (ASCC3).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Activating signal cointegrator 1 complex subunit 3 (ASCC3).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Activating signal cointegrator 1 complex subunit 3 (ASCC3).	[10]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Activating signal cointegrator 1 complex subunit 3 (ASCC3).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Activating signal cointegrator 1 complex subunit 3 (ASCC3).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Activating signal cointegrator 1 complex subunit 3 (ASCC3).	[14]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Activating signal cointegrator 1 complex subunit 3 (ASCC3).	[15]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Activating signal cointegrator 1 complex subunit 3 (ASCC3).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Activating signal cointegrator 1 complex subunit 3 (ASCC3).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Activating signal cointegrator 1 complex subunit 3 (ASCC3).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Activating signal cointegrator 1 complex subunit 3 (ASCC3).	[18]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Activating signal cointegrator 1 complex subunit 3 (ASCC3).	[19]

References

• [1] DNA unwinding by ASCC3 helicase is coupled to ALKBH3-dependent DNA alkylation repair and cancer cell proliferation.Mol Cell. 2011 Nov 4;44(3):373-84. doi: 10.1016/j.molcel.2011.08.039.
• [2] DEAD box protein DDX1 promotes colorectal tumorigenesis through transcriptional activation of the LGR5 gene.Cancer Sci. 2018 Aug;109(8):2479-2489. doi: 10.1111/cas.13661. Epub 2018 Jul 17.
• [3] Correlations between ASCC3 Gene Polymorphisms and Chronic Hepatitis B in a Chinese Han Population.PLoS One. 2015 Nov 4;10(11):e0141861. doi: 10.1371/journal.pone.0141861. eCollection 2015.
• [4] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [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] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [10] 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.
• [11] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [12] 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.
• [13] 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.
• [14] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [15] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [16] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [17] 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.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [19] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.