Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT90AZTX)

• DOT Name: SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A containing DEAD/H box 1 (SMARCAD1)
• Synonyms: EC 3.6.4.12; ATP-dependent helicase 1; hHEL1
• Gene Name: SMARCAD1
• Related Disease:
  Ectodermal dysplasia
  Advanced cancer
  Invasive breast carcinoma
  Isolated congenital adermatoglyphia
  Neoplasm
  Non-insulin dependent diabetes
  Prostate cancer
  Prostate neoplasm
  Tuberculosis
  Pancreatic cancer
  Absence of fingerprints-congenital milia syndrome
  Palmoplantar keratoderma-sclerodactyly syndrome
  Breast cancer
  Breast carcinoma
  Leiomyosarcoma
• UniProt ID: SMRCD_HUMAN
• PDB ID: 6H3A; 6QU1; 7Z36
• EC Number: 3.6.4.12
• Pfam ID: PF00271 ; PF00176
• Sequence:
  MNLFNLDRFRFEKRNKIEEAPEATPQPSQPGPSSPISLSAEEENAEGEVSRANTPDSDIT
  EKTEDSSVPETPDNERKASISYFKNQRGIQYIDLSSDSEDVVSPNCSNTVQEKTFNKDTV
  IIVSEPSEDEESQGLPTMARRNDDISELEDLSELEDLKDAKLQTLKELFPQRSDNDLLKL
  IESTSTMDGAIAAALLMFGDAGGGPRKRKLSSSSEPYEEDEFNDDQSIKKTRLDHGEESN
  ESAESSSNWEKQESIVLKLQKEFPNFDKQELREVLKEHEWMYTEALESLKVFAEDQDMQY
  VSQSEVPNGKEVSSRSQNYPKNATKTKLKQKFSMKAQNGFNKKRKKNVFNPKRVVEDSEY
  DSGSDVGSSLDEDYSSGEEVMEDGYKGKILHFLQDASIGELTLIPQCSQKKAQKITELRP
  FNSWEALFTKMSKTNGLSEDLIWHCKTLIQERDVVIRLMNKCEDISNKLTKQVTMLTGNG
  GGWNIEQPSILNQSLSLKPYQKVGLNWLALVHKHGLNGILADEMGLGKTIQAIAFLAYLY
  QEGNNGPHLIVVPASTIDNWLREVNLWCPTLKVLCYYGSQEERKQIRFNIHSRYEDYNVI
  VTTYNCAISSSDDRSLFRRLKLNYAIFDEGHMLKNMGSIRYQHLMTINANNRLLLTGTPV
  QNNLLELMSLLNFVMPHMFSSSTSEIRRMFSSKTKSADEQSIYEKERIAHAKQIIKPFIL
  RRVKEEVLKQLPPKKDRIELCAMSEKQEQLYLGLFNRLKKSINNLEKNTEMCNVMMQLRK
  MANHPLLHRQYYTAEKLKEMSQLMLKEPTHCEANPDLIFEDMEVMTDFELHVLCKQYRHI
  NNFQLDMDLILDSGKFRVLGCILSELKQKGDRVVLFSQFTMMLDILEVLLKHHQHRYLRL
  DGKTQISERIHLIDEFNTDMDIFVFLLSTKAGGLGINLTSANVVILHDIDCNPYNDKQAE
  DRCHRVGQTKEVLVIKLISQGTIEESMLKINQQKLKLEQDMTTVDEGDEGSMPADIATLL
  KTSMGL
• Function: DNA helicase that possesses intrinsic ATP-dependent nucleosome-remodeling activity and is both required for DNA repair and heterochromatin organization. Promotes DNA end resection of double-strand breaks (DSBs) following DNA damage: probably acts by weakening histone DNA interactions in nucleosomes flanking DSBs. Required for the restoration of heterochromatin organization after replication. Acts at replication sites to facilitate the maintenance of heterochromatin by directing H3 and H4 histones deacetylation, H3 'Lys-9' trimethylation (H3K9me3) and restoration of silencing.
• Tissue Specificity: Isoform 1 is expressed ubiquitously. Isoform 3 is expressed mainly in skin and esophagus. Expressed in fibroblasts and keratinocytes (at protein level) .
• KEGG Pathway: Sig.ling pathways regulating pluripotency of stem cells (hsa04550)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ectodermal dysplasia	DISLRS4M	Definitive	Autosomal dominant	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Invasive breast carcinoma	DISANYTW	Strong	Biomarker	[3]
Isolated congenital adermatoglyphia	DISRDXZX	Strong	Autosomal dominant	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[6]
Prostate cancer	DISF190Y	Strong	Biomarker	[7]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[7]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[8]
Pancreatic cancer	DISJC981	moderate	Biomarker	[9]
Absence of fingerprints-congenital milia syndrome	DIS3FVC0	Supportive	Autosomal dominant	[10]
Palmoplantar keratoderma-sclerodactyly syndrome	DIS6AGQ2	Supportive	Autosomal dominant	[1]
Breast cancer	DIS7DPX1	Limited	Biomarker	[5]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[5]
Leiomyosarcoma	DIS6COXM	Limited	Genetic Variation	[11]

4 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 SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A containing DEAD/H box 1 (SMARCAD1).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A containing DEAD/H box 1 (SMARCAD1).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A containing DEAD/H box 1 (SMARCAD1).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A containing DEAD/H box 1 (SMARCAD1).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A containing DEAD/H box 1 (SMARCAD1).	[14]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A containing DEAD/H box 1 (SMARCAD1).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A containing DEAD/H box 1 (SMARCAD1).	[14]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A containing DEAD/H box 1 (SMARCAD1).	[14]

References

• [1] SMARCAD1 Haploinsufficiency Underlies Huriez Syndrome and Associated Skin Cancer?Susceptibility. J Invest Dermatol. 2018 Jun;138(6):1428-1431. doi: 10.1016/j.jid.2018.01.015. Epub 2018 Feb 1.
• [2] The novel protein complex with SMARCAD1/KIAA1122 binds to the vicinity of TSS.J Mol Biol. 2008 Oct 3;382(2):257-65. doi: 10.1016/j.jmb.2008.07.031. Epub 2008 Jul 17.
• [3] SMARCAD1 knockdown uncovers its role in breast cancer cell migration, invasion, and metastasis.Expert Opin Ther Targets. 2016 Sep;20(9):1035-43. doi: 10.1080/14728222.2016.1195059. Epub 2016 Jun 13.
• [4] A mutation in a skin-specific isoform of SMARCAD1 causes autosomal-dominant adermatoglyphia. Am J Hum Genet. 2011 Aug 12;89(2):302-7. doi: 10.1016/j.ajhg.2011.07.004. Epub 2011 Aug 4.
• [5] SMARCAD1 in Breast Cancer Progression.Cell Physiol Biochem. 2018;50(2):489-500. doi: 10.1159/000494163. Epub 2018 Oct 11.
• [6] Genome-Wide Assessment for RestingHeart Rate and Shared Genetics WithCardiometabolic Traits and Type 2 Diabetes.J Am Coll Cardiol. 2019 Oct 29;74(17):2162-2174. doi: 10.1016/j.jacc.2019.08.1055.
• [7] The long tail of oncogenic drivers in prostate cancer.Nat Genet. 2018 May;50(5):645-651. doi: 10.1038/s41588-018-0078-z. Epub 2018 Apr 2.
• [8] GSTM1 and GSTT1 genetic polymorphisms and risk of anti-tuberculosis drug-induced hepatotoxicity: an updated meta-analysis.Eur J Clin Microbiol Infect Dis. 2013 Jul;32(7):859-68. doi: 10.1007/s10096-013-1831-y. Epub 2013 Feb 2.
• [9] SMARCAD1 Promotes Pancreatic Cancer Cell Growth and Metastasis through Wnt/-catenin-Mediated EMT.Int J Biol Sci. 2019 Jan 1;15(3):636-646. doi: 10.7150/ijbs.29562. eCollection 2019.
• [10] Genome-wide linkage analysis and whole-genome sequencing identify a recurrent SMARCAD1 variant in a unique Chinese family with Basan syndrome. Eur J Hum Genet. 2016 Aug;24(9):1367-70. doi: 10.1038/ejhg.2016.15. Epub 2016 Mar 2.
• [11] SMARCAD1, a novel human helicase family-defining member associated with genetic instability: cloning, expression, and mapping to 4q22-q23, a band rich in breakpoints and deletion mutants involved in several human diseases.Genomics. 2000 Oct 15;69(2):162-73. doi: 10.1006/geno.2000.6281.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [17] 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.