Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJTTGS0)

• DOT Name: Centrin-2 (CETN2)
• Synonyms: Caltractin isoform 1
• Gene Name: CETN2
• Related Disease:
  Neoplasm
  Xeroderma pigmentosum group C
  Astrocytoma
  Autoimmune lymphoproliferative syndrome type 1
  Ciliopathy
  Hydrocephalus
  Male infertility
  Meningioma
  Metastatic malignant neoplasm
  Retinoblastoma
  Xeroderma pigmentosum
• UniProt ID: CETN2_HUMAN
• PDB ID: 1M39; 1ZMZ; 2A4J; 2GGM; 2K2I; 2OBH; 8EBS; 8EBT; 8EBV; 8EBW; 8EBX; 8J07
• Pfam ID: PF13499
• Sequence:
  MASNFKKANMASSSQRKRMSPKPELTEEQKQEIREAFDLFDADGTGTIDVKELKVAMRAL
  GFEPKKEEIKKMISEIDKEGTGKMNFGDFLTVMTQKMSEKDTKEEILKAFKLFDDDETGK
  ISFKNLKRVAKELGENLTDEELQEMIDEADRDGDGEVSEQEFLRIMKKTSLY
• Function: Plays a fundamental role in microtubule organizing center structure and function. Required for centriole duplication and correct spindle formation. Has a role in regulating cytokinesis and genome stability via cooperation with CALM1 and CCP110.; Involved in global genome nucleotide excision repair (GG-NER) by acting as component of the XPC complex. Cooperatively with RAD23B appears to stabilize XPC. In vitro, stimulates DNA binding of the XPC:RAD23B dimer.; The XPC complex is proposed to represent the first factor bound at the sites of DNA damage and together with other core recognition factors, XPA, RPA and the TFIIH complex, is part of the pre-incision (or initial recognition) complex. The XPC complex recognizes a wide spectrum of damaged DNA characterized by distortions of the DNA helix such as single-stranded loops, mismatched bubbles or single-stranded overhangs. The orientation of XPC complex binding appears to be crucial for inducing a productive NER. XPC complex is proposed to recognize and to interact with unpaired bases on the undamaged DNA strand which is followed by recruitment of the TFIIH complex and subsequent scanning for lesions in the opposite strand in a 5'-to-3' direction by the NER machinery. Cyclobutane pyrimidine dimers (CPDs) which are formed upon UV-induced DNA damage esacpe detection by the XPC complex due to a low degree of structural perurbation. Instead they are detected by the UV-DDB complex which in turn recruits and cooperates with the XPC complex in the respective DNA repair.; As a component of the TREX-2 complex, involved in the export of mRNAs to the cytoplasm through the nuclear pores.
• KEGG Pathway: Nucleotide excision repair (hsa03420)
• Reactome Pathway:
  SUMOylation of DNA damage response and repair proteins (R-HSA-3108214)
  Loss of Nlp from mitotic centrosomes (R-HSA-380259)
  Recruitment of mitotic centrosome proteins and complexes (R-HSA-380270)
  Loss of proteins required for interphase microtubule organization from the centrosome (R-HSA-380284)
  Recruitment of NuMA to mitotic centrosomes (R-HSA-380320)
  Anchoring of the basal body to the plasma membrane (R-HSA-5620912)
  DNA Damage Recognition in GG-NER (R-HSA-5696394)
  Formation of Incision Complex in GG-NER (R-HSA-5696395)
  AURKA Activation by TPX2 (R-HSA-8854518)
  Regulation of PLK1 Activity at G2/M Transition (R-HSA-2565942)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Xeroderma pigmentosum group C	DIS8DQXS	Definitive	Biomarker	[2]
Astrocytoma	DISL3V18	Strong	Altered Expression	[3]
Autoimmune lymphoproliferative syndrome type 1	DISAFGRA	Strong	Biomarker	[4]
Ciliopathy	DIS10G4I	Strong	Biomarker	[5]
Hydrocephalus	DISIZUF7	Strong	Biomarker	[5]
Male infertility	DISY3YZZ	Strong	Biomarker	[6]
Meningioma	DISPT4TG	Strong	Altered Expression	[3]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[7]
Retinoblastoma	DISVPNPB	Strong	Altered Expression	[8]
Xeroderma pigmentosum	DISQ9H19	Strong	Biomarker	[9]

2 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 Centrin-2 (CETN2).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Centrin-2 (CETN2).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Centrin-2 (CETN2).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Centrin-2 (CETN2).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Centrin-2 (CETN2).	[13]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Centrin-2 (CETN2).	[14]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Centrin-2 (CETN2).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Centrin-2 (CETN2).	[16]
Scriptaid	DM9JZ21	Preclinical	Scriptaid affects the expression of Centrin-2 (CETN2).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Centrin-2 (CETN2).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Centrin-2 (CETN2).	[20]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Centrin-2 (CETN2).	[21]

References

• [1] Mechanisms of topoisomerase I (TOP1) gene copy number increase in a stage III colorectal cancer patient cohort.PLoS One. 2013;8(4):e60613. doi: 10.1371/journal.pone.0060613. Epub 2013 Apr 5.
• [2] Centrin 2 stimulates nucleotide excision repair by interacting with xeroderma pigmentosum group C protein.Mol Cell Biol. 2005 Jul;25(13):5664-74. doi: 10.1128/MCB.25.13.5664-5674.2005.
• [3] Differential expression of centrosome-associated proteins in human brain tumors: a possible role of hNinein isoform 6 in cell differentiation.Biofactors. 2012 Nov-Dec;38(6):470-7. doi: 10.1002/biof.1053. Epub 2012 Oct 10.
• [4] Screening for key genes associated with invasive ductal carcinoma of the breast via microarray data analysis.Genet Mol Res. 2014 Sep 29;13(3):7919-25. doi: 10.4238/2014.September.29.5.
• [5] Centrin 2 is required for mouse olfactory ciliary trafficking and development of ependymal cilia planar polarity.J Neurosci. 2014 Apr 30;34(18):6377-88. doi: 10.1523/JNEUROSCI.0067-14.2014.
• [6] Deletion of both centrin 2 (CETN2) and CETN3 destabilizes the distal connecting cilium of mouse photoreceptors.J Biol Chem. 2019 Mar 15;294(11):3957-3973. doi: 10.1074/jbc.RA118.006371. Epub 2019 Jan 15.
• [7] Alteration in gene expression profile and biological behavior in human lung cancer cell line NL9980 by nm23-H1 gene silencing.Biochem Biophys Res Commun. 2008 Jul 4;371(3):425-30. doi: 10.1016/j.bbrc.2008.04.083. Epub 2008 Apr 25.
• [8] Expression of centrin isoforms in the mammalian retina.Exp Cell Res. 1998 Jul 10;242(1):10-7. doi: 10.1006/excr.1998.4038.
• [9] Xeroderma pigmentosum group C protein possesses a high affinity binding site to human centrin 2 and calmodulin.J Biol Chem. 2003 Oct 10;278(41):40252-61. doi: 10.1074/jbc.M302546200. Epub 2003 Jul 30.
• [10] 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.
• [11] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] 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.
• [15] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] 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.
• [18] Histone deacetylase inhibitor scriptaid induces cell cycle arrest and epigenetic change in colon cancer cells. Int J Oncol. 2008 Oct;33(4):767-76.
• [19] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [20] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [21] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.