Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ4J391)

• DOT Name: Centromere protein S (CENPS)
• Synonyms: CENP-S; Apoptosis-inducing TAF9-like domain-containing protein 1; FANCM-associated histone fold protein 1; FANCM-interacting histone fold protein 1; Fanconi anemia-associated polypeptide of 16 kDa
• Gene Name: CENPS
• Related Disease:
  Chromosomal disorder
  Melanoma
  Neoplasm
  Uveal Melanoma
  Neuroblastoma
• UniProt ID: CENPS_HUMAN
• PDB ID: 4DRA; 4DRB; 4E44; 4E45; 4NDY; 4NE1; 4NE3; 4NE5; 4NE6; 7R5S; 7XHN; 7XHO; 7YWX
• Pfam ID: PF15630
• Sequence:
  MEEEAETEEQQRFSYQQRLKAAVHYTVGCLCEEVALDKEMQFSKQTIAAISELTFRQCEN
  FAKDLEMFARHAKRTTINTEDVKLLARRSNSLLKYITDKSEEIAQINLERKAQKKKKSED
  GSKNSRQPAEAGVVESEN
• Function: DNA-binding component of the Fanconi anemia (FA) core complex. Required for the normal activation of the FA pathway, leading to monoubiquitination of the FANCI-FANCD2 complex in response to DNA damage, cellular resistance to DNA cross-linking drugs, and prevention of chromosomal breakage. In complex with CENPX (MHF heterodimer), crucial cofactor for FANCM in both binding and ATP-dependent remodeling of DNA. Stabilizes FANCM. In complex with CENPX and FANCM (but not other FANC proteins), rapidly recruited to blocked forks and promotes gene conversion at blocked replication forks. In complex with CENPT, CENPW and CENPX (CENP-T-W-S-X heterotetramer), involved in the formation of a functional kinetochore outer plate, which is essential for kinetochore-microtubule attachment and faithful mitotic progression. As a component of MHF and CENP-T-W-S-X complexes, binds DNA and bends it to form a nucleosome-like structure. DNA-binding function is fulfilled in the presence of CENPX, with the following preference for DNA substates: Holliday junction > double-stranded > splay arm > single-stranded. Does not bind DNA on its own.
• Tissue Specificity: Ubiquitously expressed.
• KEGG Pathway: Fanconi anemia pathway (hsa03460)
• Reactome Pathway:
  Separation of Sister Chromatids (R-HSA-2467813)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  RHO GTPases Activate Formins (R-HSA-5663220)
  Deposition of new CENPA-containing nucleosomes at the centromere (R-HSA-606279)
  Fanconi Anemia Pathway (R-HSA-6783310)
  Mitotic Prometaphase (R-HSA-68877)
  EML4 and NUDC in mitotic spindle formation (R-HSA-9648025)
  PKR-mediated signaling (R-HSA-9833482)
  Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal (R-HSA-141444)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chromosomal disorder	DISM5BB5	Strong	Altered Expression	[1]
Melanoma	DIS1RRCY	Strong	Altered Expression	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Uveal Melanoma	DISA7ZGL	Strong	Biomarker	[2]
Neuroblastoma	DISVZBI4	moderate	Genetic Variation	[3]

12 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Centromere protein S (CENPS).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Centromere protein S (CENPS).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Centromere protein S (CENPS).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Centromere protein S (CENPS).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Centromere protein S (CENPS).	[8]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Centromere protein S (CENPS).	[9]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Centromere protein S (CENPS).	[10]
Aspirin	DM672AH	Approved	Aspirin increases the expression of Centromere protein S (CENPS).	[11]
Paclitaxel	DMLB81S	Approved	Paclitaxel increases the expression of Centromere protein S (CENPS).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Centromere protein S (CENPS).	[13]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Centromere protein S (CENPS).	[15]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of Centromere protein S (CENPS).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Centromere protein S (CENPS).	[14]

References

• [1] MHF1-MHF2, a histone-fold-containing protein complex, participates in the Fanconi anemia pathway via FANCM.Mol Cell. 2010 Mar 26;37(6):879-86. doi: 10.1016/j.molcel.2010.01.036.
• [2] Expression of APITD1 is not related to copy number changes of chromosomal region 1p36 or the prognosis of uveal melanoma.Invest Ophthalmol Vis Sci. 2007 Nov;48(11):4919-23. doi: 10.1167/iovs.07-0061.
• [3] A novel 1p36.2 located gene, APITD1, with tumour-suppressive properties and a putative p53-binding domain, shows low expression in neuroblastoma tumours.Br J Cancer. 2004 Sep 13;91(6):1119-30. doi: 10.1038/sj.bjc.6602083.
• [4] 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.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [8] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [9] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [10] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [11] Effects of aspirin on metastasis-associated gene expression detected by cDNA microarray. Acta Pharmacol Sin. 2004 Oct;25(10):1327-33.
• [12] Marked regression of liver metastasis by combined therapy of ultrasound-mediated NF kappaB-decoy transfer and transportal injection of paclitaxel, in mouse. Int J Cancer. 2008 Apr 1;122(7):1645-56. doi: 10.1002/ijc.23280.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [15] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [16] 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.