Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT91M6N4)

DOT Name Structural maintenance of chromosomes protein 5 (SMC5)
Synonyms SMC protein 5; SMC-5; hSMC5
Gene Name SMC5
Related Disease
Atelis syndrome 2 ( )
Cervical cancer ( )
Cervical carcinoma ( )
Hepatitis B virus infection ( )
Neoplasm ( )
Progressive multifocal leukoencephalopathy ( )
Pulmonary disease ( )
Sexually transmitted infection ( )
Hepatocellular carcinoma ( )
Herpes simplex infection ( )
UniProt ID
SMC5_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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Pfam ID
PF02463
Sequence
MATPSKKTSTPSPQPSKRALPRDPSSEVPSKRKNSAPQLPLLQSSGPFVEGSIVRISMEN
FLTYDICEVSPGPHLNMIVGANGTGKSSIVCAICLGLAGKPAFMGRADKVGFFVKRGCSR
GMVEIELFRASGNLVITREIDVAKNQSFWFINKKSTTQKIVEEKVAALNIQVGNLCQFLP
QDKVGEFAKLSKIELLEATEKSIGPPEMHKYHCELKNLREKEKQLETSCKEKTEYLQKMV
QRNERYKQDVERFYERKRHLDLIEMLEAKRPWVEYENVRQEYEEVKLVRDRVKEEVRKLK
EGQIPVTCRIEEMENERHNLEARIKEKATDIKEASQKCKQKQDVIERKDKHIEELQQALI
VKQNEELDRQRRIGNTRKMIEDLQNELKTTENCENLQPQIDAITNDLRRIQDEKALCEGE
IIDKRRERETLEKEKKSVDDHIVRFDNLMNQKEDKLRQRFRDTYDAVLWLRNNRDKFKQR
VCEPIMLTINMKDNKNAKYIENHIPSNDLRAFVFESQEDMEVFLKEVRDNKKLRVNAVIA
PKSSYADKAPSRSLNELKQYGFFSYLRELFDAPDPVMSYLCCQYHIHEVPVGTEKTRERI
ERVIQETRLKQIYTAEEKYVVKTSFYSNKVISSNTSLKVAQFLTVTVDLEQRRHLEEQLK
EIHRKLQAVDSGLIALRETSKHLEHKDNELRQKKKELLERKTKKRQLEQKISSKLGSLKL
MEQDTCNLEEEERKASTKIKEINVQKAKLVTELTNLIKICTSLHIQKVDLILQNTTVISE
KNKLESDYMAASSQLRLTEQHFIELDENRQRLLQKCKELMKRARQVCNLGAEQTLPQEYQ
TQVPTIPNGHNSSLPMVFQDLPNTLDEIDALLTEERSRASCFTGLNPTIVQEYTKREEEI
EQLTEELKGKKVELDQYRENISQVKERWLNPLKELVEKINEKFSNFFSSMQCAGEVDLHT
ENEEDYDKYGIRIRVKFRSSTQLHELTPHHQSGGERSVSTMLYLMALQELNRCPFRVVDE
INQGMDPINERRVFEMVVNTACKENTSQYFFITPKLLQNLPYSEKMTVLFVYNGPHMLEP
NTWNLKAFQRRRRRITFTQPS
Function
Core component of the SMC5-SMC6 complex, a complex involved in repair of DNA double-strand breaks by homologous recombination. The complex may promote sister chromatid homologous recombination by recruiting the SMC1-SMC3 cohesin complex to double-strand breaks. The complex is required for telomere maintenance via recombination in ALT (alternative lengthening of telomeres) cell lines and mediates sumoylation of shelterin complex (telosome) components which is proposed to lead to shelterin complex disassembly in ALT-associated PML bodies (APBs). Required for recruitment of telomeres to PML nuclear bodies. Required for sister chromatid cohesion during prometaphase and mitotic progression; the function seems to be independent of SMC6. SMC5-SMC6 complex may prevent transcription of episomal DNA, such as circular viral DNA genome.
Tissue Specificity Widely expressed . Strongly expressed in testis .
Reactome Pathway
SUMOylation of DNA damage response and repair proteins (R-HSA-3108214 )

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Atelis syndrome 2 DISWIFB9 Strong Autosomal recessive [1]
Cervical cancer DISFSHPF Strong Biomarker [2]
Cervical carcinoma DIST4S00 Strong Biomarker [2]
Hepatitis B virus infection DISLQ2XY Strong Biomarker [3]
Neoplasm DISZKGEW Strong Altered Expression [3]
Progressive multifocal leukoencephalopathy DISX02WS Strong Biomarker [4]
Pulmonary disease DIS6060I Strong Genetic Variation [5]
Sexually transmitted infection DISIVIAL Strong Biomarker [2]
Hepatocellular carcinoma DIS0J828 moderate Altered Expression [3]
Herpes simplex infection DISL1SAV Limited Biomarker [6]
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⏷ Show the Full List of 10 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
3 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 Structural maintenance of chromosomes protein 5 (SMC5). [7]
TAK-243 DM4GKV2 Phase 1 TAK-243 increases the sumoylation of Structural maintenance of chromosomes protein 5 (SMC5). [19]
PMID28870136-Compound-52 DMFDERP Patented PMID28870136-Compound-52 decreases the phosphorylation of Structural maintenance of chromosomes protein 5 (SMC5). [21]
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15 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 Structural maintenance of chromosomes protein 5 (SMC5). [8]
Tretinoin DM49DUI Approved Tretinoin decreases the expression of Structural maintenance of chromosomes protein 5 (SMC5). [9]
Doxorubicin DMVP5YE Approved Doxorubicin increases the expression of Structural maintenance of chromosomes protein 5 (SMC5). [10]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate increases the expression of Structural maintenance of chromosomes protein 5 (SMC5). [11]
Cisplatin DMRHGI9 Approved Cisplatin decreases the expression of Structural maintenance of chromosomes protein 5 (SMC5). [12]
Arsenic trioxide DM61TA4 Approved Arsenic trioxide increases the expression of Structural maintenance of chromosomes protein 5 (SMC5). [13]
Testosterone enanthate DMB6871 Approved Testosterone enanthate affects the expression of Structural maintenance of chromosomes protein 5 (SMC5). [14]
Tamibarotene DM3G74J Phase 3 Tamibarotene affects the expression of Structural maintenance of chromosomes protein 5 (SMC5). [9]
Genistein DM0JETC Phase 2/3 Genistein decreases the expression of Structural maintenance of chromosomes protein 5 (SMC5). [15]
Tocopherol DMBIJZ6 Phase 2 Tocopherol decreases the expression of Structural maintenance of chromosomes protein 5 (SMC5). [16]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the expression of Structural maintenance of chromosomes protein 5 (SMC5). [17]
Leflunomide DMR8ONJ Phase 1 Trial Leflunomide decreases the expression of Structural maintenance of chromosomes protein 5 (SMC5). [18]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 decreases the expression of Structural maintenance of chromosomes protein 5 (SMC5). [20]
Trichostatin A DM9C8NX Investigative Trichostatin A decreases the expression of Structural maintenance of chromosomes protein 5 (SMC5). [22]
Coumestrol DM40TBU Investigative Coumestrol decreases the expression of Structural maintenance of chromosomes protein 5 (SMC5). [23]
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⏷ Show the Full List of 15 Drug(s)

References

1 Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy. Nat Commun. 2022 Nov 4;13(1):6664. doi: 10.1038/s41467-022-34349-8.
2 The SMC5/6 Complex Interacts with the Papillomavirus E2 Protein and Influences Maintenance of Viral Episomal DNA.J Virol. 2018 Jul 17;92(15):e00356-18. doi: 10.1128/JVI.00356-18. Print 2018 Aug 1.
3 Hepatitis B virus replicating in hepatocellular carcinoma encodes HBx variants with preserved ability to antagonize restriction by Smc5/6.Antiviral Res. 2019 Dec;172:104618. doi: 10.1016/j.antiviral.2019.104618. Epub 2019 Oct 7.
4 Telomeric DNA mediates de novo PML body formation.Mol Biol Cell. 2009 Nov;20(22):4804-15. doi: 10.1091/mbc.e09-04-0309. Epub 2009 Sep 30.
5 Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease.J Clin Invest. 2016 Aug 1;126(8):2881-92. doi: 10.1172/JCI82890. Epub 2016 Jul 18.
6 PJA1 Coordinates with the SMC5/6 Complex To Restrict DNA Viruses and Episomal Genes in an Interferon-Independent Manner.J Virol. 2018 Oct 29;92(22):e00825-18. doi: 10.1128/JVI.00825-18. Print 2018 Nov 15.
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 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.
9 Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
10 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.
11 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
12 Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
13 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.
14 Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
15 Changes in gene expressions elicited by physiological concentrations of genistein on human endometrial cancer cells. Mol Carcinog. 2006 Oct;45(10):752-63.
16 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.
17 Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
18 Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
19 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.
20 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.
21 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.
22 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.
23 Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.