Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPY965Y)

• DOT Name: Polyribonucleotide 5'-hydroxyl-kinase Clp1 (CLP1)
• Synonyms: EC 2.7.1.78; Polyadenylation factor Clp1; Polynucleotide kinase Clp1; Pre-mRNA cleavage complex II protein Clp1
• Gene Name: CLP1
• Related Disease:
  Isolated congenital microcephaly
  Myopathy
  Neuromuscular disease
  Pontocerebellar hypoplasia type 10
• UniProt ID: CLP1_HUMAN
• PDB ID: 8HMY; 8HMZ
• EC Number: 2.7.1.78
• Pfam ID: PF06807 ; PF16573 ; PF16575
• Sequence:
  MGEEANDDKKPTTKFELERETELRFEVEASQSVQLELLTGMAEIFGTELTRNKKFTFDAG
  AKVAVFTWHGCSVQLSGRTEVAYVSKDTPMLLYLNTHTALEQMRRQAEKEEERGPRVMVV
  GPTDVGKSTVCRLLLNYAVRLGRRPTYVELDVGQGSVSIPGTMGALYIERPADVEEGFSI
  QAPLVYHFGSTTPGTNIKLYNKITSRLADVFNQRCEVNRRASVSGCVINTCGWVKGSGYQ
  ALVHAASAFEVDVVVVLDQERLYNELKRDLPHFVRTVLLPKSGGVVERSKDFRRECRDER
  IREYFYGFRGCFYPHAFNVKFSDVKIYKVGAPTIPDSCLPLGMSQEDNQLKLVPVTPGRD
  MVHHLLSVSTAEGTEENLSETSVAGFIVVTSVDLEHQVFTVLSPAPRPLPKNFLLIMDIR
  FMDLK
• Function: Polynucleotide kinase that can phosphorylate the 5'-hydroxyl groups of double-stranded RNA (dsRNA), single-stranded RNA (ssRNA), double-stranded DNA (dsDNA) and double-stranded DNA:RNA hybrids. dsRNA is phosphorylated more efficiently than dsDNA, and the RNA component of a DNA:RNA hybrid is phosphorylated more efficiently than the DNA component. Plays a key role in both tRNA splicing and mRNA 3'-end formation. Component of the tRNA splicing endonuclease complex: phosphorylates the 5'-terminus of the tRNA 3'-exon during tRNA splicing; this phosphorylation event is a prerequisite for the subsequent ligation of the two exon halves and the production of a mature tRNA. Its role in tRNA splicing and maturation is required for cerebellar development. Component of the pre-mRNA cleavage complex II (CF-II), which seems to be required for mRNA 3'-end formation. Also phosphorylates the 5'-terminus of exogenously introduced short interfering RNAs (siRNAs), which is a necessary prerequisite for their incorporation into the RNA-induced silencing complex (RISC). However, endogenous siRNAs and microRNAs (miRNAs) that are produced by the cleavage of dsRNA precursors by DICER1 already contain a 5'-phosphate group, so this protein may be dispensible for normal RNA-mediated gene silencing.
• KEGG Pathway: mR. surveillance pathway (hsa03015)
• Reactome Pathway:
  mRNA 3'-end processing (R-HSA-72187)
  Processing of Capped Intron-Containing Pre-mRNA (R-HSA-72203)
  RNA Polymerase II Transcription Termination (R-HSA-73856)
  Processing of Intronless Pre-mRNAs (R-HSA-77595)
  tRNA processing in the nucleus (R-HSA-6784531)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Isolated congenital microcephaly	DISUXHZ6	Strong	Biomarker	[1]
Myopathy	DISOWG27	Strong	Altered Expression	[2]
Neuromuscular disease	DISQTIJZ	Strong	Biomarker	[1]
Pontocerebellar hypoplasia type 10	DISSA24T	Strong	Autosomal recessive	[1]

5 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 Polyribonucleotide 5'-hydroxyl-kinase Clp1 (CLP1).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Polyribonucleotide 5'-hydroxyl-kinase Clp1 (CLP1).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Polyribonucleotide 5'-hydroxyl-kinase Clp1 (CLP1).	[7]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Polyribonucleotide 5'-hydroxyl-kinase Clp1 (CLP1).	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Polyribonucleotide 5'-hydroxyl-kinase Clp1 (CLP1).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Polyribonucleotide 5'-hydroxyl-kinase Clp1 (CLP1).	[4]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Polyribonucleotide 5'-hydroxyl-kinase Clp1 (CLP1).	[6]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Polyribonucleotide 5'-hydroxyl-kinase Clp1 (CLP1).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Polyribonucleotide 5'-hydroxyl-kinase Clp1 (CLP1).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Polyribonucleotide 5'-hydroxyl-kinase Clp1 (CLP1).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Polyribonucleotide 5'-hydroxyl-kinase Clp1 (CLP1).	[13]
CATECHIN	DMY38SB	Investigative	CATECHIN decreases the expression of Polyribonucleotide 5'-hydroxyl-kinase Clp1 (CLP1).	[14]

References

• [1] Human CLP1 mutations alter tRNA biogenesis, affecting both peripheral and central nervous system function. Cell. 2014 Apr 24;157(3):636-50. doi: 10.1016/j.cell.2014.02.058.
• [2] The atypical calpains: evolutionary analyses and roles in Caenorhabditis elegans cellular degeneration.PLoS Genet. 2012;8(3):e1002602. doi: 10.1371/journal.pgen.1002602. Epub 2012 Mar 29.
• [3] 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.
• [4] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [5] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [6] 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.
• [7] 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.
• [8] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [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.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] Epicatechin and a cocoa polyphenolic extract modulate gene expression in human Caco-2 cells. J Nutr. 2004 Oct;134(10):2509-16.