Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTE9V7D9)

• DOT Name: DNA excision repair protein ERCC-6-like (ERCC6L)
• Synonyms: EC 3.6.4.12; ATP-dependent helicase ERCC6-like; PLK1-interacting checkpoint helicase; Tumor antigen BJ-HCC-15
• Gene Name: ERCC6L
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Clear cell renal carcinoma
  Colorectal carcinoma
  Epithelial neoplasm
  Immunodeficiency
  Neoplasm
  Renal cell carcinoma
  Triple negative breast cancer
  Kidney cancer
• UniProt ID: ERC6L_HUMAN
• PDB ID: 5JNO
• EC Number: 3.6.4.12
• Pfam ID: PF00271 ; PF00176
• Sequence:
  MEASRRFPEAEALSPEQAAHYLRYVKEAKEATKNGDLEEAFKLFNLAKDIFPNEKVLSRI
  QKIQEALEELAEQGDDEFTDVCNSGLLLYRELHNQLFEHQKEGIAFLYSLYRDGRKGGIL
  ADDMGLGKTVQIIAFLSGMFDASLVNHVLLIMPTNLINTWVKEFIKWTPGMRVKTFHGPS
  KDERTRNLNRIQQRNGVIITTYQMLINNWQQLSSFRGQEFVWDYVILDEAHKIKTSSTKS
  AICARAIPASNRLLLTGTPIQNNLQELWSLFDFACQGSLLGTLKTFKMEYENPITRAREK
  DATPGEKALGFKISENLMAIIKPYFLRRTKEDVQKKKSSNPEARLNEKNPDVDAICEMPS
  LSRKNDLIIWIRLVPLQEEIYRKFVSLDHIKELLMETRSPLAELGVLKKLCDHPRLLSAR
  ACCLLNLGTFSAQDGNEGEDSPDVDHIDQVTDDTLMEESGKMIFLMDLLKRLRDEGHQTL
  VFSQSRQILNIIERLLKNRHFKTLRIDGTVTHLLEREKRINLFQQNKDYSVFLLTTQVGG
  VGLTLTAATRVVIFDPSWNPATDAQAVDRVYRIGQKENVVVYRLITCGTVEEKIYRRQVF
  KDSLIRQTTGEKKNPFRYFSKQELRELFTIEDLQNSVTQLQLQSLHAAQRKSDIKLDEHI
  AYLQSLGIAGISDHDLMYTCDLSVKEELDVVEESHYIQQRVQKAQFLVEFESQNKEFLME
  QQRTRNEGAWLREPVFPSSTKKKCPKLNKPQPQPSPLLSTHHTQEEDISSKMASVVIDDL
  PKEGEKQDLSSIKVNVTTLQDGKGTGSADSIATLPKGFGSVEELCTNSSLGMEKSFATKN
  EAVQKETLQEGPKQEALQEDPLESFNYVLSKSTKADIGPNLDQLKDDEILRHCNPWPIIS
  ITNESQNAESNVSIIEIADDLSASHSALQDAQASEAKLEEEPSASSPQYACDFNLFLEDS
  ADNRQNFSSQSLEHVEKENSLCGSAPNSRAGFVHSKTCLSWEFSEKDDEPEEVVVKAKIR
  SKARRIVSDGEDEDDSFKDTSSINPFNTSLFQFSSVKQFDASTPKNDISPPGRFFSSQIP
  SSVNKSMNSRRSLASRRSLINMVLDHVEDMEERLDDSSEAKGPEDYPEEGVEESSGEASK
  YTEEDPSGETLSSENKSSWLMTSKPSALAQETSLGAPEPLSGEQLVGSPQDKAAEATNDY
  ETLVKRGKELKECGKIQEALNCLVKALDIKSADPEVMLLTLSLYKQLNNN
• Function: DNA helicase that acts as a tension sensor that associates with catenated DNA which is stretched under tension until it is resolved during anaphase. Functions as ATP-dependent DNA translocase. Can promote Holliday junction branch migration (in vitro).
• Reactome Pathway:
  Separation of Sister Chromatids (R-HSA-2467813)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  RHO GTPases Activate Formins (R-HSA-5663220)
  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

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[1]
Epithelial neoplasm	DIS0T594	Strong	Altered Expression	[4]
Immunodeficiency	DIS093I0	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[3]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[2]
Kidney cancer	DISBIPKM	moderate	Altered Expression	[5]

19 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 DNA excision repair protein ERCC-6-like (ERCC6L).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DNA excision repair protein ERCC-6-like (ERCC6L).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of DNA excision repair protein ERCC-6-like (ERCC6L).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of DNA excision repair protein ERCC-6-like (ERCC6L).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of DNA excision repair protein ERCC-6-like (ERCC6L).	[10]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of DNA excision repair protein ERCC-6-like (ERCC6L).	[11]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of DNA excision repair protein ERCC-6-like (ERCC6L).	[12]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of DNA excision repair protein ERCC-6-like (ERCC6L).	[12]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of DNA excision repair protein ERCC-6-like (ERCC6L).	[13]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of DNA excision repair protein ERCC-6-like (ERCC6L).	[14]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of DNA excision repair protein ERCC-6-like (ERCC6L).	[15]
Lucanthone	DMZLBUO	Approved	Lucanthone decreases the expression of DNA excision repair protein ERCC-6-like (ERCC6L).	[16]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of DNA excision repair protein ERCC-6-like (ERCC6L).	[17]
PEITC	DMOMN31	Phase 2	PEITC decreases the expression of DNA excision repair protein ERCC-6-like (ERCC6L).	[18]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of DNA excision repair protein ERCC-6-like (ERCC6L).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of DNA excision repair protein ERCC-6-like (ERCC6L).	[21]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of DNA excision repair protein ERCC-6-like (ERCC6L).	[23]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of DNA excision repair protein ERCC-6-like (ERCC6L).	[10]
Manganese	DMKT129	Investigative	Manganese decreases the expression of DNA excision repair protein ERCC-6-like (ERCC6L).	[25]

4 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 DNA excision repair protein ERCC-6-like (ERCC6L).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of DNA excision repair protein ERCC-6-like (ERCC6L).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of DNA excision repair protein ERCC-6-like (ERCC6L).	[24]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of DNA excision repair protein ERCC-6-like (ERCC6L).	[22]

References

• [1] ERCC6L promotes cell growth and invasion in human colorectal cancer.Oncol Lett. 2019 Jul;18(1):237-246. doi: 10.3892/ol.2019.10297. Epub 2019 Apr 30.
• [2] Loss of PICH promotes chromosome instability and cell death in triple-negative breast cancer.Cell Death Dis. 2019 Jun 3;10(6):428. doi: 10.1038/s41419-019-1662-6.
• [3] ERCC6L that is up-regulated in high grade of renal cell carcinoma enhances cell viability in vitro and promotes tumor growth in vivo potentially through modulating MAPK signalling pathway.Cancer Gene Ther. 2019 Sep;26(9-10):323-333. doi: 10.1038/s41417-018-0064-8. Epub 2018 Nov 21.
• [4] Activation of hedgehog signaling and its association with cisplatin resistance in ovarian epithelial tumors.Oncol Lett. 2018 Apr;15(4):5569-5576. doi: 10.3892/ol.2018.8008. Epub 2018 Feb 9.
• [5] ERCC6L, a DNA helicase, is involved in cell proliferation and associated with survival and progress in breast and kidney cancers.Oncotarget. 2017 Jun 27;8(26):42116-42124. doi: 10.18632/oncotarget.14998.
• [6] Inter-laboratory comparison of human renal proximal tubule (HK-2) transcriptome alterations due to Cyclosporine A exposure and medium exhaustion. Toxicol In Vitro. 2009 Apr;23(3):486-99.
• [7] 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.
• [8] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [11] 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.
• [12] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [13] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [14] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [15] Methotrexate modulates folate phenotype and inflammatory profile in EA.hy 926 cells. Eur J Pharmacol. 2014 Jun 5;732:60-7.
• [16] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [17] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [18] Phenethyl isothiocyanate alters the gene expression and the levels of protein associated with cell cycle regulation in human glioblastoma GBM 8401 cells. Environ Toxicol. 2017 Jan;32(1):176-187.
• [19] 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.
• [20] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [21] 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.
• [22] 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.
• [23] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [24] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [25] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.