Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5GR4Z2)

• DOT Name: SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5 (SMARCA5)
• Synonyms: SWI/SNF-related matrix-associated actin-dependent regulator of chromatin A5; EC 3.6.4.-; Sucrose nonfermenting protein 2 homolog; hSNF2H
• Gene Name: SMARCA5
• Related Disease:
  Acute leukaemia
  Acute myelogenous leukaemia
  Anemia
  Complex neurodevelopmental disorder
  Gastric cancer
  Glioma
  Hemolytic anemia
  Hepatitis
  Hepatitis A virus infection
  Hepatitis B virus infection
  Herpes simplex infection
  leukaemia
  Leukemia
  Liver cirrhosis
  Non-small-cell lung cancer
  Prostate cancer
  Prostate carcinoma
  Stomach cancer
  Breast cancer
  Breast carcinoma
  Ewing sarcoma
  Plasma cell myeloma
  Primitive neuroectodermal tumor
  Advanced cancer
  Hepatocellular carcinoma
  Neurodevelopmental disorder
• UniProt ID: SMCA5_HUMAN
• PDB ID: 6NE3
• EC Number: 3.6.4.-
• Pfam ID: PF09110 ; PF00271 ; PF09111 ; PF00176
• Sequence:
  MSSAAEPPPPPPPESAPSKPAASIASGGSNSSNKGGPEGVAAQAVASAASAGPADAEMEE
  IFDDASPGKQKEIQEPDPTYEEKMQTDRANRFEYLLKQTELFAHFIQPAAQKTPTSPLKM
  KPGRPRIKKDEKQNLLSVGDYRHRRTEQEEDEELLTESSKATNVCTRFEDSPSYVKWGKL
  RDYQVRGLNWLISLYENGINGILADEMGLGKTLQTISLLGYMKHYRNIPGPHMVLVPKST
  LHNWMSEFKRWVPTLRSVCLIGDKEQRAAFVRDVLLPGEWDVCVTSYEMLIKEKSVFKKF
  NWRYLVIDEAHRIKNEKSKLSEIVREFKTTNRLLLTGTPLQNNLHELWSLLNFLLPDVFN
  SADDFDSWFDTNNCLGDQKLVERLHMVLRPFLLRRIKADVEKSLPPKKEVKIYVGLSKMQ
  REWYTRILMKDIDILNSAGKMDKMRLLNILMQLRKCCNHPYLFDGAEPGPPYTTDMHLVT
  NSGKMVVLDKLLPKLKEQGSRVLIFSQMTRVLDILEDYCMWRNYEYCRLDGQTPHDERQD
  SINAYNEPNSTKFVFMLSTRAGGLGINLATADVVILYDSDWNPQVDLQAMDRAHRIGQTK
  TVRVFRFITDNTVEERIVERAEMKLRLDSIVIQQGRLVDQNLNKIGKDEMLQMIRHGATH
  VFASKESEITDEDIDGILERGAKKTAEMNEKLSKMGESSLRNFTMDTESSVYNFEGEDYR
  EKQKIAFTEWIEPPKRERKANYAVDAYFREALRVSEPKAPKAPRPPKQPNVQDFQFFPPR
  LFELLEKEILFYRKTIGYKVPRNPELPNAAQAQKEEQLKIDEAESLNDEELEEKEKLLTQ
  GFTNWNKRDFNQFIKANEKWGRDDIENIAREVEGKTPEEVIEYSAVFWERCNELQDIEKI
  MAQIERGEARIQRRISIKKALDTKIGRYKAPFHQLRISYGTNKGKNYTEEEDRFLICMLH
  KLGFDKENVYDELRQCIRNSPQFRFDWFLKSRTAMELQRRCNTLITLIERENMELEEKEK
  AEKKKRGPKPSTQKRKMDGAPDGRGRKKKLKL
• Function: Helicase that possesses intrinsic ATP-dependent nucleosome-remodeling activity. Catalytic subunit of ISWI chromatin-remodeling complexes, which form ordered nucleosome arrays on chromatin and facilitate access to DNA during DNA-templated processes such as DNA replication, transcription, and repair; this may require intact histone H4 tails. Within the ISWI chromatin-remodeling complexes, slides edge- and center-positioned histone octamers away from their original location on the DNA template. Catalytic activity and histone octamer sliding propensity is regulated and determined by components of the ISWI chromatin-remodeling complexes. The BAZ1A/ACF1-, BAZ1B/WSTF-, BAZ2A/TIP5- and BAZ2B-containing ISWI chromatin-remodeling complexes regulate the spacing of nucleosomes along the chromatin and have the ability to slide mononucleosomes to the center of a DNA template in an ATP-dependent manner. The CECR2- and RSF1-containing ISWI chromatin-remodeling complexes do not have the ability to slide mononucleosomes to the center of a DNA template. Binds to core histones together with RSF1, and is required for the assembly of regular nucleosome arrays by the RSF-5 ISWI chromatin-remodeling complex. Involved in DNA replication and together with BAZ1A/ACF1 is required for replication of pericentric heterochromatin in S-phase. Probably plays a role in repression of RNA polymerase I dependent transcription of the rDNA locus, through the recruitment of the SIN3/HDAC1 corepressor complex to the rDNA promoter. Essential component of the WICH-5 ISWI chromatin-remodeling complex (also called the WICH complex), a chromatin-remodeling complex that mobilizes nucleosomes and reconfigures irregular chromatin to a regular nucleosomal array structure. The WICH-5 ISWI chromatin-remodeling complex regulates the transcription of various genes, has a role in RNA polymerase I transcription. Within the B-WICH complex has a role in RNA polymerase III transcription. Mediates the histone H2AX phosphorylation at 'Tyr-142', and is involved in the maintenance of chromatin structures during DNA replication processes. Essential component of NoRC-5 ISWI chromatin-remodeling complex, a complex that mediates silencing of a fraction of rDNA by recruiting histone-modifying enzymes and DNA methyltransferases, leading to heterochromatin formation and transcriptional silencing.
• Tissue Specificity: Ubiquitously expressed.
• KEGG Pathway: ATP-dependent chromatin remodeling (hsa03082)
• Reactome Pathway:
  B-WICH complex positively regulates rRNA expression (R-HSA-5250924)
  Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks (R-HSA-5693565)
  Deposition of new CENPA-containing nucleosomes at the centromere (R-HSA-606279)
  NoRC negatively regulates rRNA expression (R-HSA-427413)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute leukaemia	DISDQFDI	Strong	Biomarker	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[1]
Anemia	DISTVL0C	Strong	Biomarker	[2]
Complex neurodevelopmental disorder	DISB9AFI	Strong	Autosomal dominant	[3]
Gastric cancer	DISXGOUK	Strong	Posttranslational Modification	[4]
Glioma	DIS5RPEH	Strong	Altered Expression	[5]
Hemolytic anemia	DIS803XQ	Strong	Altered Expression	[1]
Hepatitis	DISXXX35	Strong	Biomarker	[6]
Hepatitis A virus infection	DISUMFQV	Strong	Biomarker	[6]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[7]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[8]
leukaemia	DISS7D1V	Strong	Biomarker	[9]
Leukemia	DISNAKFL	Strong	Biomarker	[9]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[6]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[10]
Prostate cancer	DISF190Y	Strong	Biomarker	[11]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[11]
Stomach cancer	DISKIJSX	Strong	Posttranslational Modification	[4]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[12]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[12]
Ewing sarcoma	DISQYLV3	moderate	Altered Expression	[13]
Plasma cell myeloma	DIS0DFZ0	moderate	Altered Expression	[14]
Primitive neuroectodermal tumor	DISFHXHA	moderate	Genetic Variation	[13]
Advanced cancer	DISAT1Z9	Limited	Genetic Variation	[15]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[6]
Neurodevelopmental disorder	DIS372XH	Limited	Biomarker	[16]

14 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 member 5 (SMARCA5).	[17]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5 (SMARCA5).	[18]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5 (SMARCA5).	[19]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5 (SMARCA5).	[20]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5 (SMARCA5).	[21]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5 (SMARCA5).	[22]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5 (SMARCA5).	[23]
Selenium	DM25CGV	Approved	Selenium decreases the expression of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5 (SMARCA5).	[24]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5 (SMARCA5).	[25]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial decreases the expression of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5 (SMARCA5).	[26]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium decreases the expression of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5 (SMARCA5).	[26]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5 (SMARCA5).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5 (SMARCA5).	[29]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5 (SMARCA5).	[30]

2 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 decreases the sumoylation of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5 (SMARCA5).	[27]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5 (SMARCA5).	[28]

References

• [1] Chromatin remodeling gene SMARCA5 is dysregulated in primitive hematopoietic cells of acute leukemia.Leukemia. 2000 Jul;14(7):1247-52. doi: 10.1038/sj.leu.2401807.
• [2] The ISWI ATPase Smarca5 (Snf2h) Is Required for Proliferation and Differentiation of Hematopoietic Stem and Progenitor Cells.Stem Cells. 2017 Jun;35(6):1614-1623. doi: 10.1002/stem.2604. Epub 2017 Apr 15.
• [3] 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.
• [4] SMARCA5 methylation and expression in gastric cancer.Cancer Invest. 2011 Feb;29(2):162-6. doi: 10.3109/07357907.2010.543365.
• [5] Overexpression of hSNF2H in glioma promotes cell proliferation, invasion, and chemoresistance through its interaction with Rsf-1.Tumour Biol. 2016 Jun;37(6):7203-12. doi: 10.1007/s13277-015-4579-4. Epub 2015 Dec 14.
• [6] Using circular RNA SMARCA5 as a potential novel biomarker for hepatocellular carcinoma.Clin Chim Acta. 2019 May;492:37-44. doi: 10.1016/j.cca.2019.02.001. Epub 2019 Feb 2.
• [7] Overexpression of a chromatin remodeling factor, RSF-1/HBXAP, correlates with aggressive oral squamous cell carcinoma.Am J Pathol. 2011 May;178(5):2407-15. doi: 10.1016/j.ajpath.2011.01.043.
• [8] Cellular SNF2H chromatin-remodeling factor promotes herpes simplex virus 1 immediate-early gene expression and replication.mBio. 2011 Jan 18;2(1):e00330-10. doi: 10.1128/mBio.00330-10.
• [9] Epigenetic control of SPI1 gene by CTCF and ISWI ATPase SMARCA5.PLoS One. 2014 Feb 3;9(2):e87448. doi: 10.1371/journal.pone.0087448. eCollection 2014.
• [10] Circular RNA SMARCA5 inhibits the proliferation, migration, and invasion of non-small cell lung cancer by miR-19b-3p/HOXA9 axis.Onco Targets Ther. 2019 Aug 30;12:7055-7065. doi: 10.2147/OTT.S216320. eCollection 2019.
• [11] Androgen-responsive circular RNA circSMARCA5 is up-regulated and promotes cell proliferation in prostate cancer.Biochem Biophys Res Commun. 2017 Nov 25;493(3):1217-1223. doi: 10.1016/j.bbrc.2017.07.162. Epub 2017 Jul 29.
• [12] Overexpression of SMARCA5 correlates with cell proliferation and migration in breast cancer.Tumour Biol. 2015 Mar;36(3):1895-902. doi: 10.1007/s13277-014-2791-2. Epub 2014 Nov 7.
• [13] A novel t(4;22)(q31;q12) produces an EWSR1-SMARCA5 fusion in extraskeletal Ewing sarcoma/primitive neuroectodermal tumor.Mod Pathol. 2011 Mar;24(3):333-42. doi: 10.1038/modpathol.2010.201. Epub 2010 Nov 26.
• [14] Circ-SMARCA5 suppresses progression of multiple myeloma by targeting miR-767-5p.BMC Cancer. 2019 Oct 10;19(1):937. doi: 10.1186/s12885-019-6088-0.
• [15] A basic motif anchoring ISWI to nucleosome acidic patch regulates nucleosome spacing.Nat Chem Biol. 2020 Feb;16(2):134-142. doi: 10.1038/s41589-019-0413-4. Epub 2019 Dec 9.
• [16] The role of ISWI chromatin remodeling complexes in brain development and neurodevelopmental disorders.Mol Cell Neurosci. 2018 Mar;87:55-64. doi: 10.1016/j.mcn.2017.10.008. Epub 2017 Dec 15.
• [17] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [18] 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.
• [19] Effect of all-trans retinoic acid on sodium/iodide symporter expression, radioiodine uptake and gene expression profiles in a human anaplastic thyroid carcinoma cell line. Nucl Med Biol. 2006 Oct;33(7):875-82. doi: 10.1016/j.nucmedbio.2006.07.004.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [24] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [25] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [26] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.