Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT81JS6K)

• DOT Name: Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN
• Synonyms: DNA helicase, RecQ-like type 3; RecQ protein-like 2; Werner syndrome protein
• Gene Name: WRN
• Related Disease:
  Werner syndrome
  Osteosarcoma
• UniProt ID: WRN_HUMAN
• PDB ID: 2AXL; 2DGZ; 2E1E; 2E1F; 2FBT; 2FBV; 2FBX; 2FBY; 2FC0; 3AAF; 6TYV; 6YHR; 7XUT
• EC Number: 3.1.-.-; 5.6.2.4
• Pfam ID: PF00270 ; PF01612 ; PF00271 ; PF00570 ; PF14493 ; PF16124 ; PF09382
• Sequence:
  MSEKKLETTAQQRKCPEWMNVQNKRCAVEERKACVRKSVFEDDLPFLEFTGSIVYSYDAS
  DCSFLSEDISMSLSDGDVVGFDMEWPPLYNRGKLGKVALIQLCVSESKCYLFHVSSMSVF
  PQGLKMLLENKAVKKAGVGIEGDQWKLLRDFDIKLKNFVELTDVANKKLKCTETWSLNSL
  VKHLLGKQLLKDKSIRCSNWSKFPLTEDQKLYAATDAYAGFIIYRNLEILDDTVQRFAIN
  KEEEILLSDMNKQLTSISEEVMDLAKHLPHAFSKLENPRRVSILLKDISENLYSLRRMII
  GSTNIETELRPSNNLNLLSFEDSTTGGVQQKQIREHEVLIHVEDETWDPTLDHLAKHDGE
  DVLGNKVERKEDGFEDGVEDNKLKENMERACLMSLDITEHELQILEQQSQEEYLSDIAYK
  STEHLSPNDNENDTSYVIESDEDLEMEMLKHLSPNDNENDTSYVIESDEDLEMEMLKSLE
  NLNSGTVEPTHSKCLKMERNLGLPTKEEEEDDENEANEGEEDDDKDFLWPAPNEEQVTCL
  KMYFGHSSFKPVQWKVIHSVLEERRDNVAVMATGYGKSLCFQYPPVYVGKIGLVISPLIS
  LMEDQVLQLKMSNIPACFLGSAQSENVLTDIKLGKYRIVYVTPEYCSGNMGLLQQLEADI
  GITLIAVDEAHCISEWGHDFRDSFRKLGSLKTALPMVPIVALTATASSSIREDIVRCLNL
  RNPQITCTGFDRPNLYLEVRRKTGNILQDLQPFLVKTSSHWEFEGPTIIYCPSRKMTQQV
  TGELRKLNLSCGTYHAGMSFSTRKDIHHRFVRDEIQCVIATIAFGMGINKADIRQVIHYG
  APKDMESYYQEIGRAGRDGLQSSCHVLWAPADINLNRHLLTEIRNEKFRLYKLKMMAKME
  KYLHSSRCRRQIILSHFEDKQVQKASLGIMGTEKCCDNCRSRLDHCYSMDDSEDTSWDFG
  PQAFKLLSAVDILGEKFGIGLPILFLRGSNSQRLADQYRRHSLFGTGKDQTESWWKAFSR
  QLITEGFLVEVSRYNKFMKICALTKKGRNWLHKANTESQSLILQANEELCPKKLLLPSSK
  TVSSGTKEHCYNQVPVELSTEKKSNLEKLYSYKPCDKISSGSNISKKSIMVQSPEKAYSS
  SQPVISAQEQETQIVLYGKLVEARQKHANKMDVPPAILATNKILVDMAKMRPTTVENVKR
  IDGVSEGKAAMLAPLLEVIKHFCQTNSVQTDLFSSTKPQEEQKTSLVAKNKICTLSQSMA
  ITYSLFQEKKMPLKSIAESRILPLMTIGMHLSQAVKAGCPLDLERAGLTPEVQKIIADVI
  RNPPVNSDMSKISLIRMLVPENIDTYLIHMAIEILKHGPDSGLQPSCDVNKRRCFPGSEE
  ICSSSKRSKEEVGINTETSSAERKRRLPVWFAKGSDTSKKLMDKTKRGGLFS
• Function: Multifunctional enzyme that has magnesium and ATP-dependent 3'-5' DNA-helicase activity on partially duplex substrates. Also has 3'->5' exonuclease activity towards double-stranded DNA with a 5'-overhang. Has no nuclease activity towards single-stranded DNA or blunt-ended double-stranded DNA. Helicase activity is most efficient with (d)ATP, but (d)CTP will substitute with reduced efficiency; strand displacement is enhanced by single-strand binding-protein (heterotrimeric replication protein A complex, RPA1, RPA2, RPA3). Binds preferentially to DNA substrates containing alternate secondary structures, such as replication forks and Holliday junctions. May play an important role in the dissociation of joint DNA molecules that can arise as products of homologous recombination, at stalled replication forks or during DNA repair. Alleviates stalling of DNA polymerases at the site of DNA lesions. Important for genomic integrity. Plays a role in the formation of DNA replication focal centers; stably associates with foci elements generating binding sites for RP-A. Plays a role in double-strand break repair after gamma-irradiation. Depletion leads to chromosomal breaks and genome instability.
• Reactome Pathway:
  Removal of the Flap Intermediate from the C-strand (R-HSA-174437)
  SUMOylation of DNA damage response and repair proteins (R-HSA-3108214)
  HDR through Single Strand Annealing (SSA) (R-HSA-5685938)
  HDR through Homologous Recombination (HRR) (R-HSA-5685942)
  Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA) (R-HSA-5693554)
  Resolution of D-loop Structures through Holliday Junction Intermediates (R-HSA-5693568)
  Homologous DNA Pairing and Strand Exchange (R-HSA-5693579)
  Processing of DNA double-strand break ends (R-HSA-5693607)
  Presynaptic phase of homologous DNA pairing and strand exchange (R-HSA-5693616)
  Regulation of TP53 Activity through Phosphorylation (R-HSA-6804756)
  G2/M DNA damage checkpoint (R-HSA-69473)
  Defective homologous recombination repair (HRR) due to BRCA1 loss of function (R-HSA-9701192)
  Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function (R-HSA-9704331)
  Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function (R-HSA-9704646)
  Impaired BRCA2 binding to RAD51 (R-HSA-9709570)
  Impaired BRCA2 binding to PALB2 (R-HSA-9709603)
  Processive synthesis on the C-strand of the telomere (R-HSA-174414)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Werner syndrome	DISZY45W	Definitive	Autosomal recessive	[1]
Osteosarcoma	DISLQ7E2	Moderate	Autosomal recessive	[2]

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydroquinone	DM6AVR4	Approved	Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN increases the response to substance of Hydroquinone.	[15]
Etoposide	DMNH3PG	Approved	Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN increases the response to substance of Etoposide.	[16]
Amsacrine	DMZKYIV	Approved	Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN increases the response to substance of Amsacrine.	[16]
8-hydroxyguanine	DMT9BPN	Investigative	Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN decreases the response to substance of 8-hydroxyguanine.	[17]

8 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 Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN.	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN.	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN.	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN.	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN.	[7]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN.	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN.	[9]
OXYBENZONE	DMMZYX6	Investigative	OXYBENZONE increases the expression of Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN.	[14]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Resveratrol	DM3RWXL	Phase 3	Resveratrol affects the localization of Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN.	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN.	[11]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN.	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN.	[13]

References

• [1] 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.
• [2] Germline and somatic genetics of osteosarcoma - connecting aetiology, biology and therapy. Nat Rev Endocrinol. 2017 Aug;13(8):480-491. doi: 10.1038/nrendo.2017.16. Epub 2017 Mar 24.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [5] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [6] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [7] 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.
• [8] Arsenic exposure, telomere length, and expression of telomere-related genes among Bangladeshi individuals. Environ Res. 2015 Jan;136:462-9. doi: 10.1016/j.envres.2014.09.040. Epub 2014 Nov 25.
• [9] A comprehensive analysis of Wnt/beta-catenin signaling pathway-related genes and crosstalk pathways in the treatment of As2O3 in renal cancer. Ren Fail. 2018 Nov;40(1):331-339.
• [10] Resveratrol induces senescence-like growth inhibition of U-2 OS cells associated with the instability of telomeric DNA and upregulation of BRCA1. Mech Ageing Dev. 2009 Aug;130(8):528-37. doi: 10.1016/j.mad.2009.06.005. Epub 2009 Jun 25.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Chromatin modifiers: A new class of pollutants with potential epigenetic effects revealed by in vitro assays and transcriptomic analyses. Toxicology. 2023 Jan 15;484:153413. doi: 10.1016/j.tox.2022.153413. Epub 2022 Dec 26.
• [15] Comparison of proliferation and genomic instability responses to WRN silencing in hematopoietic HL60 and TK6 cells. PLoS One. 2011 Jan 18;6(1):e14546. doi: 10.1371/journal.pone.0014546.
• [16] Werner's syndrome lymphoblastoid cells are hypersensitive to topoisomerase II inhibitors in the G2 phase of the cell cycle. Mutat Res. 2000 Mar 20;459(2):123-33. doi: 10.1016/s0921-8777(99)00065-8.
• [17] Action-at-a-distance mutagenesis induced by oxidized guanine in Werner syndrome protein-reduced human cells. Chem Res Toxicol. 2015 Apr 20;28(4):621-8. doi: 10.1021/tx500418m. Epub 2015 Mar 2.