Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG1RAKJ)

• DOT Name: Centromere protein X (CENPX)
• Synonyms: CENP-X; FANCM-associated histone fold protein 2; FANCM-interacting histone fold protein 2; Fanconi anemia-associated polypeptide of 10 kDa; Retinoic acid-inducible gene D9 protein homolog; Stimulated by retinoic acid gene 13 protein homolog
• Gene Name: CENPX
• Related Disease:
  Advanced cancer
  Clear cell renal carcinoma
  Common variable immunodeficiency
  Fanconi anemia complementation group A
  Fanconi's anemia
  Gastric cancer
  Hyperglycemia
  Non-insulin dependent diabetes
  Pancreatic cancer
  Splenic marginal zone lymphoma
  Stomach cancer
• UniProt ID: CENPX_HUMAN
• PDB ID: 4DRA; 4DRB; 4E44; 4E45; 4NDY; 4NE1; 4NE3; 4NE5; 4NE6; 7R5S; 7XHN; 7XHO; 7YWX
• Pfam ID: PF09415
• Sequence:
  MEGAGAGSGFRKELVSRLLHLHFKDDKTKVSGDALQLMVELLKVFVVEAAVRGVRQAQAE
  DALRVDVDQLEKVLPQLLLDF
• 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 CENPS (MHF heterodimer), crucial cofactor for FANCM in both binding and ATP-dependent remodeling of DNA. Stabilizes FANCM. In complex with CENPS and FANCM (but not other FANC proteins), rapidly recruited to blocked forks and promotes gene conversion at blocked replication forks. In complex with CENPS, CENPT and CENPW (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 CENPS, with the following preference for DNA substates: Holliday junction > double-stranded > splay arm > single-stranded. Does not bind DNA on its own.
• KEGG Pathway: Fanconi anemia pathway (hsa03460)
• Reactome Pathway:
  Fanconi Anemia Pathway (R-HSA-6783310)
  PKR-mediated signaling (R-HSA-9833482)
  Deposition of new CENPA-containing nucleosomes at the centromere (R-HSA-606279)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[2]
Common variable immunodeficiency	DISHE7JQ	Strong	Altered Expression	[3]
Fanconi anemia complementation group A	DIS8PZLI	Strong	Biomarker	[4]
Fanconi's anemia	DISGW6Q8	Strong	Biomarker	[4]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[5]
Hyperglycemia	DIS0BZB5	Strong	Biomarker	[6]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[6]
Pancreatic cancer	DISJC981	Strong	Biomarker	[7]
Splenic marginal zone lymphoma	DISCGTZY	Strong	Altered Expression	[3]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[5]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Centromere protein X (CENPX) affects the response to substance of Fluorouracil.	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Centromere protein X (CENPX).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Centromere protein X (CENPX).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Centromere protein X (CENPX).	[9]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Centromere protein X (CENPX).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Centromere protein X (CENPX).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Centromere protein X (CENPX).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Centromere protein X (CENPX).	[14]

References

• [1] Basic helix-loop-helix transcription factors DEC1 and DEC2 regulate the paclitaxel-induced apoptotic pathway of MCF-7 human breast cancer cells.Int J Mol Med. 2011 Apr;27(4):491-5. doi: 10.3892/ijmm.2011.617. Epub 2011 Feb 14.
• [2] Regulation of STRA13 by the von Hippel-Lindau tumor suppressor protein, hypoxia, and the UBC9/ubiquitin proteasome degradation pathway.J Biol Chem. 2001 May 4;276(18):15306-15. doi: 10.1074/jbc.M010516200. Epub 2001 Feb 6.
• [3] Clonal expansion and functional exhaustion of monoclonal marginal zone B cells in mixed cryoglobulinemia: the yin and yang of HCV-driven lymphoproliferation and autoimmunity.Autoimmun Rev. 2013 Jan;12(3):430-5. doi: 10.1016/j.autrev.2012.08.016. Epub 2012 Aug 23.
• [4] 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.
• [5] The hypoxia-regulated transcription factor DEC1 (Stra13, SHARP-2) and its expression in gastric cancer.OMICS. 2009 Aug;13(4):301-6. doi: 10.1089/omi.2009.0014.
• [6] Therapeutic Silencing of Centromere Protein X Ameliorates Hyperglycemia in Zebrafish and Mouse Models of Type 2 Diabetes Mellitus.Front Genet. 2019 Jul 29;10:693. doi: 10.3389/fgene.2019.00693. eCollection 2019.
• [7] Identification of genes differentially induced by hypoxia in pancreatic cancer cells.Biochem Biophys Res Commun. 2001 Nov 9;288(4):882-6. doi: 10.1006/bbrc.2001.5867.
• [8] 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.
• [9] 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.
• [10] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [11] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [12] 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.
• [13] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [15] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.