Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVJ6VE9)

• DOT Name: Centromere protein C (CENPC)
• Synonyms: CENP-C; Centromere autoantigen C; Centromere protein C 1; CENP-C 1; Interphase centromere complex protein 7
• Gene Name: CENPC
• Related Disease:
  Burkitt lymphoma
  Cardiovascular disease
  Chronic kidney disease
  Myocardial infarction
  Narcolepsy
  Scleroderma
  Systemic sclerosis
• UniProt ID: CENPC_HUMAN
• PDB ID: 5LSJ; 5LSK; 6MUO; 6MUP; 6SE6; 6SEE; 6SEF; 7PII; 7QOO; 7R5R; 7XHN; 7XHO; 7YWX; 7YYH
• Pfam ID: PF11699 ; PF15620 ; PF15622
• Sequence:
  MAASGLDHLKNGYRRRFCRPSRARDINTEQGQNVLEILQDCFEEKSLANDFSTNSTKSVP
  NSTRKIKDTCIQSPSKECQKSHPKSVPVSSKKKEASLQFVVEPSEATNRSVQAHEVHQKI
  LATDVSSKNTPDSKKISSRNINDHHSEADEEFYLSVGSPSVLLDAKTSVSQNVIPSSAQK
  RETYTFENSVNMLPSSTEVSVKTKKRLNFDDKVMLKKIEIDNKVSDEEDKTSEGQERKPS
  GSSQNRIRDSEYEIQRQAKKSFSTLFLETVKRKSESSPIVRHAATAPPHSCPPDDTKLIE
  DEFIIDESDQSFASRSWITIPRKAGSLKQRTISPAESTALLQGRKSREKHHNILPKTLAN
  DKHSHKPHPVETSQPSDKTVLDTSYALIGETVNNYRSTKYEMYSKNAEKPSRSKRTIKQK
  QRRKFMAKPAEEQLDVGQSKDENIHTSHITQDEFQRNSDRNMEEHEEMGNDCVSKKQMPP
  VGSKKSSTRKDKEESKKKRFSSESKNKLVPEEVTSTVTKSRRISRRPSDWWVVKSEESPV
  YSNSSVRNELPMHHNSSRKSTKKTNQSSKNIRKKTIPLKRQKTATKGNQRVQKFLNAEGS
  GGIVGHDEISRCSLSEPLESDEADLAKKKNLDCSRSTRSSKNEDNIMTAQNVPLKPQTSG
  YTCNIPTESNLDSGEHKTSVLEESGPSRLNNNYLMSGKNDVDDEEVHGSSDDSKQSKVIP
  KNRIHHKLVLPSNTPNVRRTKRTRLKPLEYWRGERIDYQGRPSGGFVISGVLSPDTISSK
  RKAKENIGKVNKKSNKKRICLDNDERKTNLMVNLGIPLGDPLQPTRVKDPETREIILMDL
  VRPQDTYQFFVKHGELKVYKTLDTPFFSTGKLILGPQEEKGKQHVGQDILVFYVNFGDLL
  CTLHETPYILSTGDSFYVPSGNYYNIKNLRNEESVLLFTQIKR
• Function: Component of the CENPA-NAC (nucleosome-associated) complex, a complex that plays a central role in assembly of kinetochore proteins, mitotic progression and chromosome segregation. The CENPA-NAC complex recruits the CENPA-CAD (nucleosome distal) complex and may be involved in incorporation of newly synthesized CENPA into centromeres. CENPC recruits DNA methylation and DNMT3B to both centromeric and pericentromeric satellite repeats and regulates the histone code in these regions.
• 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)
  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

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Burkitt lymphoma	DIS9D5XU	Strong	Genetic Variation	[1]
Cardiovascular disease	DIS2IQDX	Strong	Altered Expression	[2]
Chronic kidney disease	DISW82R7	Strong	Biomarker	[3]
Myocardial infarction	DIS655KI	Strong	Altered Expression	[4]
Narcolepsy	DISLCNLI	Strong	Genetic Variation	[5]
Scleroderma	DISVQ342	Strong	Biomarker	[6]
Systemic sclerosis	DISF44L6	moderate	Biomarker	[7]

4 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 Centromere protein C (CENPC).	[8]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Centromere protein C (CENPC).	[17]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Centromere protein C (CENPC).	[19]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Centromere protein C (CENPC).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Centromere protein C (CENPC).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Centromere protein C (CENPC).	[10]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Centromere protein C (CENPC).	[11]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Centromere protein C (CENPC).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Centromere protein C (CENPC).	[13]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Centromere protein C (CENPC).	[14]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Centromere protein C (CENPC).	[15]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Centromere protein C (CENPC).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Centromere protein C (CENPC).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Centromere protein C (CENPC).	[20]

References

• [1] Multiprotein complexes present at the MIF motifs flanking the promoter of the human c-myc gene.FEBS Lett. 2000 May 26;474(1):23-8. doi: 10.1016/s0014-5793(00)01562-3.
• [2] MIF family cytokines in cardiovascular diseases and prospects for precision-based therapeutics.Expert Opin Ther Targets. 2017 Jul;21(7):671-683. doi: 10.1080/14728222.2017.1336227.
• [3] Elevated MIF-2 levels predict mortality in critically ill patients.J Crit Care. 2017 Aug;40:52-57. doi: 10.1016/j.jcrc.2017.03.012. Epub 2017 Mar 16.
• [4] Macrophage Migration Inhibitory Factor (MIF) Expression Increases during Myocardial Infarction and Supports Pro-Inflammatory Signaling in Cardiac Fibroblasts.Biomolecules. 2019 Jan 23;9(2):38. doi: 10.3390/biom9020038.
• [5] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [6] CENP-C, an autoantigen in scleroderma, is a component of the human inner kinetochore plate.Cell. 1992 Jul 10;70(1):115-25. doi: 10.1016/0092-8674(92)90538-n.
• [7] Anti-centromere antibodies (ACA) in systemic sclerosis patients and their relatives: a serological and HLA study.Clin Exp Immunol. 1994 May;96(2):267-74. doi: 10.1111/j.1365-2249.1994.tb06552.x.
• [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] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [12] 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.
• [13] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [14] 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.
• [15] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [16] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [17] 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.
• [18] 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.
• [19] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [20] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.