Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ6E0HY)

DOT Name Lysine-specific demethylase 5C (KDM5C)
Synonyms EC 1.14.11.67; Histone demethylase JARID1C; Jumonji/ARID domain-containing protein 1C; Protein SmcX; Protein Xe169; -trimethyl-L-lysine(4) demethylase 5C
Gene Name KDM5C
Related Disease
Syndromic X-linked intellectual disability Claes-Jensen type ( )
X-linked syndromic intellectual disability ( )
UniProt ID
KDM5C_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
2JRZ; 5FWJ
EC Number
1.14.11.67
Pfam ID
PF01388 ; PF02373 ; PF02375 ; PF21323 ; PF00628 ; PF08429 ; PF02928
Sequence
MEPGSDDFLPPPECPVFEPSWAEFRDPLGYIAKIRPIAEKSGICKIRPPADWQPPFAVEV
DNFRFTPRIQRLNELEAQTRVKLNYLDQIAKFWEIQGSSLKIPNVERRILDLYSLSKIVV
EEGGYEAICKDRRWARVAQRLNYPPGKNIGSLLRSHYERIVYPYEMYQSGANLVQCNTRP
FDNEEKDKEYKPHSIPLRQSVQPSKFNSYGRRAKRLQPDPEPTEEDIEKNPELKKLQIYG
AGPKMMGLGLMAKDKTLRKKDKEGPECPPTVVVKEELGGDVKVESTSPKTFLESKEELSH
SPEPCTKMTMRLRRNHSNAQFIESYVCRMCSRGDEDDKLLLCDGCDDNYHIFCLLPPLPE
IPKGVWRCPKCVMAECKRPPEAFGFEQATREYTLQSFGEMADSFKADYFNMPVHMVPTEL
VEKEFWRLVNSIEEDVTVEYGADIHSKEFGSGFPVSDSKRHLTPEEEEYATSGWNLNVMP
VLEQSVLCHINADISGMKVPWLYVGMVFSAFCWHIEDHWSYSINYLHWGEPKTWYGVPSL
AAEHLEEVMKKLTPELFDSQPDLLHQLVTLMNPNTLMSHGVPVVRTNQCAGEFVITFPRA
YHSGFNQGYNFAEAVNFCTADWLPAGRQCIEHYRRLRRYCVFSHEELICKMAACPEKLDL
NLAAAVHKEMFIMVQEERRLRKALLEKGITEAEREAFELLPDDERQCIKCKTTCFLSALA
CYDCPDGLVCLSHINDLCKCSSSRQYLRYRYTLDELPAMLHKLKVRAESFDTWANKVRVA
LEVEDGRKRSLEELRALESEARERRFPNSELLQQLKNCLSEAEACVSRALGLVSGQEAGP
HRVAGLQMTLTELRAFLDQMNNLPCAMHQIGDVKGVLEQVEAYQAEAREALASLPSSPGL
LQSLLERGRQLGVEVPEAQQLQRQVEQARWLDEVKRTLAPSARRGTLAVMRGLLVAGASV
APSPAVDKAQAELQELLTIAERWEEKAHLCLEARQKHPPATLEAIIREAENIPVHLPNIQ
ALKEALAKARAWIADVDEIQNGDHYPCLDDLEGLVAVGRDLPVGLEELRQLELQVLTAHS
WREKASKTFLKKNSCYTLLEVLCPCADAGSDSTKRSRWMEKELGLYKSDTELLGLSAQDL
RDPGSVIVAFKEGEQKEKEGILQLRRTNSAKPSPLASSSTASSTTSICVCGQVLAGAGAL
QCDLCQDWFHGRCVSVPRLLSSPRPNPTSSPLLAWWEWDTKFLCPLCMRSRRPRLETILA
LLVALQRLPVRLPEGEALQCLTERAISWQGRARQALASEDVTALLGRLAELRQRLQAEPR
PEEPPNYPAAPASDPLREGSGKDMPKVQGLLENGDSVTSPEKVAPEEGSGKRDLELLSSL
LPQLTGPVLELPEATRAPLEELMMEGDLLEVTLDENHSIWQLLQAGQPPDLERIRTLLEL
EKAERHGSRARGRALERRRRRKVDRGGEGDDPAREELEPKRVRSSGPEAEEVQEEEELEE
ETGGEGPPAPIPTTGSPSTQENQNGLEPAEGTTSGPSAPFSTLTPRLHLPCPQQPPQQQL
Function
Histone demethylase that specifically demethylates 'Lys-4' of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 'Lys-9', H3 'Lys-27', H3 'Lys-36', H3 'Lys-79' or H4 'Lys-20'. Demethylates trimethylated and dimethylated but not monomethylated H3 'Lys-4'. Participates in transcriptional repression of neuronal genes by recruiting histone deacetylases and REST at neuron-restrictive silencer elements. Represses the CLOCK-BMAL1 heterodimer-mediated transcriptional activation of the core clock component PER2.
Tissue Specificity Expressed in all tissues examined. Highest levels found in brain and skeletal muscle.
Reactome Pathway
HDMs demethylate histones (R-HSA-3214842 )
BioCyc Pathway
MetaCyc:ENSG00000126012-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Syndromic X-linked intellectual disability Claes-Jensen type DISLIJL7 Definitive X-linked [1]
X-linked syndromic intellectual disability DISG1YOH Definitive X-linked [2]
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Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
7 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 Lysine-specific demethylase 5C (KDM5C). [3]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of Lysine-specific demethylase 5C (KDM5C). [4]
Decitabine DMQL8XJ Approved Decitabine increases the expression of Lysine-specific demethylase 5C (KDM5C). [6]
Bortezomib DMNO38U Approved Bortezomib decreases the expression of Lysine-specific demethylase 5C (KDM5C). [7]
Ethanol DMDRQZU Approved Ethanol decreases the expression of Lysine-specific demethylase 5C (KDM5C). [8]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 increases the expression of Lysine-specific demethylase 5C (KDM5C). [10]
Trichostatin A DM9C8NX Investigative Trichostatin A decreases the expression of Lysine-specific demethylase 5C (KDM5C). [12]
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⏷ Show the Full List of 7 Drug(s)
4 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Arsenic DMTL2Y1 Approved Arsenic affects the methylation of Lysine-specific demethylase 5C (KDM5C). [5]
TAK-243 DM4GKV2 Phase 1 TAK-243 affects the sumoylation of Lysine-specific demethylase 5C (KDM5C). [9]
PMID28870136-Compound-52 DMFDERP Patented PMID28870136-Compound-52 decreases the phosphorylation of Lysine-specific demethylase 5C (KDM5C). [11]
Coumarin DM0N8ZM Investigative Coumarin decreases the phosphorylation of Lysine-specific demethylase 5C (KDM5C). [11]
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References

1 Mutations in JARID1C are associated with X-linked mental retardation, short stature and hyperreflexia. J Med Genet. 2008 Dec;45(12):787-93. doi: 10.1136/jmg.2008.058990. Epub 2008 Aug 12.
2 Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
3 Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
4 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.
5 Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
6 Gene induction and apoptosis in human hepatocellular carci-noma cells SMMC-7721 exposed to 5-aza-2'-deoxycytidine. Chin Med J (Engl). 2007 Sep 20;120(18):1626-31.
7 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.
8 Alcohol triggered bile acid disequilibrium by suppressing BSEP to sustain hepatocellular carcinoma progression. Chem Biol Interact. 2022 Apr 1;356:109847. doi: 10.1016/j.cbi.2022.109847. Epub 2022 Feb 9.
9 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.
10 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.
11 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.
12 From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.