Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3IBHQD)

• DOT Name: Structural maintenance of chromosomes protein 6 (SMC6)
• Synonyms: SMC protein 6; SMC-6; hSMC6
• Gene Name: SMC6
• Related Disease:
  Breast cancer
  Breast carcinoma
• UniProt ID: SMC6_HUMAN
• Pfam ID: PF13476
• Sequence:
  MAKRKEENFSSPKNAKRPRQEELEDFDKDGDEDECKGTTLTAAEVGIIESIHLKNFMCHS
  MLGPFKFGSNVNFVVGNNGSGKSAVLTALIVGLGGRAVATNRGSSLKGFVKDGQNSADIS
  ITLRNRGDDAFKASVYGNSILIQQHISIDGSRSYKLKSATGSVVSTRKEELIAILDHFNI
  QVDNPVSVLTQEMSKQFLQSKNEGDKYKFFMKATQLEQMKEDYSYIMETKERTKEQIHQG
  EERLTELKRQCVEKEERFQSIAGLSTMKTNLESLKHEMAWAVVNEIEKQLNAIRDNIKIG
  EDRAARLDRKMEEQQVRLNEAEQKYKDIQDKLEKISEETNARAPECMALKADVVAKKRAY
  NEAEVLYNRSLNEYKALKKDDEQLCKRIEELKKSTDQSLEPERLERQKKISWLKERVKAF
  QNQENSVNQEIEQFQQAIEKDKEEHGKIKREELDVKHALSYNQRQLKELKDSKTDRLKRF
  GPNVPALLEAIDDAYRQGHFTYKPVGPLGACIHLRDPELALAIESCLKGLLQAYCCHNHA
  DERVLQALMKRFYLPGTSRPPIIVSEFRNEIYDVRHRAAYHPDFPTVLTALEIDNAVVAN
  SLIDMRGIETVLLIKNNSVARAVMQSQKPPKNCREAFTADGDQVFAGRYYSSENTRPKFL
  SRDVDSEISDLENEVENKTAQILNLQQHLSALEKDIKHNEELLKRCQLHYKELKMKIRKN
  ISEIRELENIEEHQSVDIATLEDEAQENKSKMKMVEEHMEQQKENMEHLKSLKIEAENKY
  DAIKFKINQLSELADPLKDELNLADSEVDNQKRGKRHYEEKQKEHLDTLNKKKRELDMKE
  KELEEKMSQARQICPERIEVEKSASILDKEINRLRQKIQAEHASHGDREEIMRQYQEARE
  TYLDLDSKVRTLKKFIKLLGEIMEHRFKTYQQFRRCLTLRCKLYFDNLLSQRAYCGKMNF
  DHKNETLSISVQPGEGNKAAFNDMRALSGGERSFSTVCFILSLWSIAESPFRCLDEFDVY
  MDMVNRRIAMDLILKMADSQRFRQFILLTPQSMSSLPSSKLIRILRMSDPERGQTTLPFR
  PVTQEEDDDQR
• Function: Core component of the SMC5-SMC6 complex, a complex involved in 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. 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

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]

12 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 Structural maintenance of chromosomes protein 6 (SMC6).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Structural maintenance of chromosomes protein 6 (SMC6).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Structural maintenance of chromosomes protein 6 (SMC6).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Structural maintenance of chromosomes protein 6 (SMC6).	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Structural maintenance of chromosomes protein 6 (SMC6).	[6]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Structural maintenance of chromosomes protein 6 (SMC6).	[7]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Structural maintenance of chromosomes protein 6 (SMC6).	[8]
Vitamin C	DMXJ7O8	Approved	Vitamin C decreases the expression of Structural maintenance of chromosomes protein 6 (SMC6).	[9]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Structural maintenance of chromosomes protein 6 (SMC6).	[10]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Structural maintenance of chromosomes protein 6 (SMC6).	[7]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Structural maintenance of chromosomes protein 6 (SMC6).	[13]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Structural maintenance of chromosomes protein 6 (SMC6).	[14]

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 increases the sumoylation of Structural maintenance of chromosomes protein 6 (SMC6).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Structural maintenance of chromosomes protein 6 (SMC6).	[12]

References

• [1] Evaluation of associations between common variation in mitotic regulatory pathways and risk of overall and high grade breast cancer.Breast Cancer Res Treat. 2011 Sep;129(2):617-22. doi: 10.1007/s10549-011-1587-y. Epub 2011 May 24.
• [2] 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.
• [3] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [4] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [5] 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.
• [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] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [8] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [9] Antiproliferative effect of ascorbic acid is associated with the inhibition of genes necessary to cell cycle progression. PLoS One. 2009;4(2):e4409.
• [10] 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.
• [11] 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.
• [12] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [13] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [14] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.