Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIP6IRN)

• DOT Name: Shugoshin 1 (SGO1)
• Synonyms: Serologically defined breast cancer antigen NY-BR-85; Shugoshin-like 1
• Gene Name: SGO1
• Related Disease: Chronic atrial and intestinal dysrhythmia
• UniProt ID: SGO1_HUMAN
• PDB ID: 3FGA; 3Q6S; 4A0I; 7ZJS
• Pfam ID: PF07557 ; PF07558
• Sequence:
  MAKERCLKKSFQDSLEDIKKRMKEKRNKNLAEIGKRRSFIAAPCQIITNTSTLLKNYQDN
  NKMLVLALENEKSKVKEAQDIILQLRKECYYLTCQLYALKGKLTSQQTVEPAQNQEICSS
  GMDPNSDDSSRNLFVKDLPQIPLEETELPGQGESFQIEDQIPTIPQDTLGVDFDSGEAKS
  TDNVLPRTVSVRSSLKKHCNSICQFDSLDDFETSHLAGKSFEFERVGFLDPLVNMHIPEN
  VQHNACQWSKDQVNLSPKLIQPGTFTKTKEDILESKSEQTKSKQRDTQERKREEKRKANR
  RKSKRMSKYKENKSENKKTVPQKKMHKSVSSNDAYNFNLEEGVHLTPFRQKVSNDSNREE
  NNESEVSLCESSGSGDDSDDLYLPTCKYIQNPTSNSDRPVTRPLAKRALKYTDEKETEGS
  KPTKTPTTTPPETQQSPHLSLKDITNVSLYPVVKIRRLSLSPKKNKASPAVALPKRRCTA
  SVNYKEPTLASKLRRGDPFTDLCFLNSPIFKQKKDLRRSKKRALEVSPAKEAIFILYYVR
  EFVSRFPDCRKCKLETHICLR
• Function: Plays a central role in chromosome cohesion during mitosis by preventing premature dissociation of cohesin complex from centromeres after prophase, when most of cohesin complex dissociates from chromosomes arms. May act by preventing phosphorylation of the STAG2 subunit of cohesin complex at the centromere, ensuring cohesin persistence at centromere until cohesin cleavage by ESPL1/separase at anaphase. Essential for proper chromosome segregation during mitosis and this function requires interaction with PPP2R1A. Its phosphorylated form is necessary for chromosome congression and for the proper attachment of spindle microtubule to the kinetochore. Necessary for kinetochore localization of PLK1 and CENPF. May play a role in the tension sensing mechanism of the spindle-assembly checkpoint by regulating PLK1 kinetochore affinity. Isoform 3 plays a role in maintaining centriole cohesion involved in controlling spindle pole integrity. Involved in centromeric enrichment of AUKRB in prometaphase.
• Tissue Specificity: Widely expressed. Highly expressed in testis. Expressed in lung, small intestine, breast, liver and placenta. Strongly overexpressed in 90% of breast cancers tested.
• KEGG Pathway:
  Cell cycle (hsa04110)
  Oocyte meiosis (hsa04114)
• Reactome Pathway:
  Separation of Sister Chromatids (R-HSA-2467813)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  RHO GTPases Activate Formins (R-HSA-5663220)
  Mitotic Prometaphase (R-HSA-68877)
  EML4 and NUDC in mitotic spindle formation (R-HSA-9648025)
  Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal (R-HSA-141444)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chronic atrial and intestinal dysrhythmia	DISJR36T	Supportive	Autosomal recessive	[1]

15 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 Shugoshin 1 (SGO1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Shugoshin 1 (SGO1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Shugoshin 1 (SGO1).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Shugoshin 1 (SGO1).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Shugoshin 1 (SGO1).	[6]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Shugoshin 1 (SGO1).	[6]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Shugoshin 1 (SGO1).	[7]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Shugoshin 1 (SGO1).	[8]
Lucanthone	DMZLBUO	Approved	Lucanthone decreases the expression of Shugoshin 1 (SGO1).	[9]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Shugoshin 1 (SGO1).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Shugoshin 1 (SGO1).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Shugoshin 1 (SGO1).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Shugoshin 1 (SGO1).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Shugoshin 1 (SGO1).	[14]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Shugoshin 1 (SGO1).	[5]

References

• [1] Mutations in SGOL1 cause a novel cohesinopathy affecting heart and gut rhythm. Nat Genet. 2014 Nov;46(11):1245-9. doi: 10.1038/ng.3113. Epub 2014 Oct 5.
• [2] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [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] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [6] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [7] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [8] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [9] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [10] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [11] Gene expression changes in human prostate carcinoma cells exposed to genotoxic and nongenotoxic aryl hydrocarbon receptor ligands. Toxicol Lett. 2011 Oct 10;206(2):178-88.
• [12] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [13] 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.
• [14] Cultured human peripheral blood mononuclear cells alter their gene expression when challenged with endocrine-disrupting chemicals. Toxicology. 2013 Jan 7;303:17-24.