Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0T4WKI)

• DOT Name: DNA excision repair protein ERCC-8 (ERCC8)
• Synonyms: Cockayne syndrome WD repeat protein CSA
• Gene Name: ERCC8
• Related Disease:
  Bacteremia
  Cockayne syndrome type 1
  Herpes simplex infection
  Angina pectoris
  Atrophic vaginitis
  Candidiasis
  Carpal tunnel syndrome
  Cerebellar ataxia
  Chromosomal disorder
  Chronic inflammatory demyelinating polyneuropathy
  Cowden disease
  Craniosynostosis 2
  Dilated cardiomyopathy 1A
  Gastric disease
  Intellectual disability
  Myocardial infarction
  Type-1/2 diabetes
  UV-sensitive syndrome 2
  Adrenoleukodystrophy
  Gastric cancer
  Methicillin-resistant staphylococci infection
  Stomach cancer
  Cockayne syndrome type 2
  UV-sensitive syndrome
  Leukodystrophy
  Malaria
  Myeloproliferative neoplasm
  Nephropathy
  Nervous system disease
  Neuroblastoma
  Premature aging syndrome
  Schizophrenia
• UniProt ID: ERCC8_HUMAN
• PDB ID: 4A11; 6FCV; 7OO3; 7OOB; 7OOP; 7OPC; 7OPD; 8B3D; 8B3F; 8B3I
• Pfam ID: PF00400
• Sequence:
  MLGFLSARQTGLEDPLRLRRAESTRRVLGLELNKDRDVERIHGGGINTLDIEPVEGRYML
  SGGSDGVIVLYDLENSSRQSYYTCKAVCSIGRDHPDVHRYSVETVQWYPHDTGMFTSSSF
  DKTLKVWDTNTLQTADVFNFEETVYSHHMSPVSTKHCLVAVGTRGPKVQLCDLKSGSCSH
  ILQGHRQEILAVSWSPRYDYILATASADSRVKLWDVRRASGCLITLDQHNGKKSQAVESA
  NTAHNGKVNGLCFTSDGLHLLTVGTDNRMRLWNSSNGENTLVNYGKVCNNSKKGLKFTVS
  CGCSSEFVFVPYGSTIAVYTVYSGEQITMLKGHYKTVDCCVFQSNFQELYSGSRDCNILA
  WVPSLYEPVPDDDETTTKSQLNPAFEDAWSSSDEEG
• Function: Substrate-recognition component of the CSA complex, a DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex, involved in transcription-coupled nucleotide excision repair. The CSA complex (DCX(ERCC8) complex) promotes the ubiquitination and subsequent proteasomal degradation of ERCC6 in a UV-dependent manner; ERCC6 degradation is essential for the recovery of RNA synthesis after transcription-coupled repair. It is required for the recruitment of XAB2, HMGN1 and TCEA1/TFIIS to a transcription-coupled repair complex which removes RNA polymerase II-blocking lesions from the transcribed strand of active genes. Plays a role in DNA single-strand and double-strand breaks (DSSBs) repair; involved in repair of DSSBs by non-homologous end joining (NHEJ).
• KEGG Pathway:
  Nucleotide excision repair (hsa03420)
  Ubiquitin mediated proteolysis (hsa04120)
• Reactome Pathway:
  Transcription-Coupled Nucleotide Excision Repair (TC-NER) (R-HSA-6781827)
  Dual incision in TC-NER (R-HSA-6782135)
  Gap-filling DNA repair synthesis and ligation in TC-NER (R-HSA-6782210)
  Neddylation (R-HSA-8951664)
  Formation of TC-NER Pre-Incision Complex (R-HSA-6781823)

Molecular Interaction Atlas (MIA) of This DOT

32 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bacteremia	DIS6N9RZ	Definitive	Genetic Variation	[1]
Cockayne syndrome type 1	DIS9JFVY	Definitive	Autosomal recessive	[2]
Herpes simplex infection	DISL1SAV	Definitive	Altered Expression	[3]
Angina pectoris	DISCLMC4	Strong	Biomarker	[4]
Atrophic vaginitis	DISOV9GB	Strong	Biomarker	[5]
Candidiasis	DISIRYMU	Strong	Biomarker	[6]
Carpal tunnel syndrome	DISHQ3BE	Strong	Biomarker	[7]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[8]
Chromosomal disorder	DISM5BB5	Strong	Biomarker	[9]
Chronic inflammatory demyelinating polyneuropathy	DISNGBLD	Strong	Biomarker	[10]
Cowden disease	DISMYKCE	Strong	Biomarker	[11]
Craniosynostosis 2	DISBJX9D	Strong	Biomarker	[12]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Biomarker	[13]
Gastric disease	DISNZNTG	Strong	Altered Expression	[14]
Intellectual disability	DISMBNXP	Strong	Biomarker	[15]
Myocardial infarction	DIS655KI	Strong	Biomarker	[16]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[7]
UV-sensitive syndrome 2	DIS7ZER1	Strong	Autosomal recessive	[17]
Adrenoleukodystrophy	DISTUD1F	moderate	Biomarker	[18]
Gastric cancer	DISXGOUK	moderate	Genetic Variation	[19]
Methicillin-resistant staphylococci infection	DIS6DRDZ	moderate	Biomarker	[20]
Stomach cancer	DISKIJSX	moderate	Genetic Variation	[19]
Cockayne syndrome type 2	DIS3X0GQ	Supportive	Autosomal recessive	[21]
UV-sensitive syndrome	DISHCN4B	Supportive	Autosomal recessive	[22]
Leukodystrophy	DISVY1TT	Limited	Genetic Variation	[15]
Malaria	DISQ9Y50	Limited	Genetic Variation	[23]
Myeloproliferative neoplasm	DIS5KAPA	Limited	Biomarker	[24]
Nephropathy	DISXWP4P	Limited	Biomarker	[25]
Nervous system disease	DISJ7GGT	Limited	Genetic Variation	[15]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[26]
Premature aging syndrome	DIS51AGT	Limited	Genetic Variation	[27]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[28]

1 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 DNA excision repair protein ERCC-8 (ERCC8).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of DNA excision repair protein ERCC-8 (ERCC8).	[30]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DNA excision repair protein ERCC-8 (ERCC8).	[31]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of DNA excision repair protein ERCC-8 (ERCC8).	[32]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of DNA excision repair protein ERCC-8 (ERCC8).	[33]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of DNA excision repair protein ERCC-8 (ERCC8).	[34]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of DNA excision repair protein ERCC-8 (ERCC8).	[31]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of DNA excision repair protein ERCC-8 (ERCC8).	[35]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of DNA excision repair protein ERCC-8 (ERCC8).	[36]

References

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• [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] Contributions of nucleotide excision repair, DNA polymerase eta, and homologous recombination to replication of UV-irradiated herpes simplex virus type 1.J Biol Chem. 2010 Apr 30;285(18):13761-8. doi: 10.1074/jbc.M110.107920. Epub 2010 Mar 9.
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• [5] Chitosan Ascorbate Nanoparticles for the Vaginal Delivery of Antibiotic Drugs in Atrophic Vaginitis.Mar Drugs. 2017 Oct 19;15(10):319. doi: 10.3390/md15100319.
• [6] Investigation of the in vitro antifungal and antibiofilm activities of ceragenins CSA-8, CSA-13, CSA-44, CSA-131, and CSA-138 against Candida species.Diagn Microbiol Infect Dis. 2018 Aug;91(4):324-330. doi: 10.1016/j.diagmicrobio.2018.03.014. Epub 2018 Mar 28.
• [7] Can ultrasound imaging be used for the diagnosis of carpal tunnel syndrome in diabetic patients? A systemic review and network meta-analysis.J Neurol. 2020 Jul;267(7):1887-1895. doi: 10.1007/s00415-019-09254-8. Epub 2019 Feb 25.
• [8] Homozygosity mapping and whole exome sequencing reveal a novel ERCC8 mutation in a Chinese consanguineous family with unique cerebellar ataxia.Clin Chim Acta. 2019 Jul;494:64-70. doi: 10.1016/j.cca.2019.03.1609. Epub 2019 Mar 12.
• [9] Genetic variation associated with chromosomal aberration frequency: A genome-wide association study.Environ Mol Mutagen. 2019 Jan;60(1):17-28. doi: 10.1002/em.22236. Epub 2018 Oct 3.
• [10] Nerve echogenicity and intranerve CSA variability in high-resolution nerve ultrasound (HRUS) in chronic inflammatory demyelinating polyneuropathy (CIDP).J Neurol. 2019 Feb;266(2):468-475. doi: 10.1007/s00415-018-9158-3. Epub 2018 Dec 15.
• [11] Mechanistic Interplay between Light Switching and Guest Binding in Photochromic [Pd(2)Dithienylethene(4)] Coordination Cages.J Am Chem Soc. 2019 Feb 6;141(5):2097-2103. doi: 10.1021/jacs.8b11872. Epub 2019 Jan 22.
• [12] Two Novel Heterozygous Mutations in ERCC8 Cause Cockayne Syndrome in a Chinese Patient.Pediatr Neurol. 2015 Sep;53(3):262-5. doi: 10.1016/j.pediatrneurol.2015.06.006. Epub 2015 Jun 14.
• [13] Association between polymorphisms of the HSPB7 gene and Cheyne-Stokes respiration with central sleep apnea in patients with dilated cardiomyopathy and congestive heart failure.Int J Cardiol. 2016 Oct 15;221:926-31. doi: 10.1016/j.ijcard.2016.07.107. Epub 2016 Jul 9.
• [14] Epistatic SNP interaction of ERCC6 with ERCC8 and their joint protein expression contribute to gastric cancer/atrophic gastritis risk.Oncotarget. 2017 Jun 27;8(26):43140-43152. doi: 10.18632/oncotarget.17814.
• [15] A possible cranio-oro-facial phenotype in Cockayne syndrome.Orphanet J Rare Dis. 2013 Jan 14;8:9. doi: 10.1186/1750-1172-8-9.
• [16] Xin-Ji-Er-Kang Alleviates Myocardial Infarction-Induced Cardiovascular Remodeling in Rats by Inhibiting Endothelial Dysfunction.Biomed Res Int. 2019 Jun 25;2019:4794082. doi: 10.1155/2019/4794082. eCollection 2019.
• [17] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [18] Predicted structures of two proteins involved in human diseases.Cell Biochem Biophys. 2001;35(1):35-47. doi: 10.1385/CBB:35:1:35.
• [19] Detection and clinical significance of DNA repair gene ERCC8 tag SNPs in gastric cancer.Turk J Gastroenterol. 2018 Jul;29(4):392-396. doi: 10.5152/tjg.2018.17662.
• [20] CSA-90 Promotes Bone Formation and Mitigates Methicillin-resistant Staphylococcus aureus Infection in a Rat Open Fracture Model.Clin Orthop Relat Res. 2018 Jun;476(6):1311-1323. doi: 10.1097/01.blo.0000533624.79802.e1.
• [21] Cockayne Syndrome. 2000 Dec 28 [updated 2019 Aug 29]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [22] A UV-sensitive syndrome patient with a specific CSA mutation reveals separable roles for CSA in response to UV and oxidative DNA damage. Proc Natl Acad Sci U S A. 2009 Apr 14;106(15):6209-14. doi: 10.1073/pnas.0902113106. Epub 2009 Mar 27.
• [23] Antibodies that inhibit binding of Plasmodium falciparum-infected erythrocytes to chondroitin sulfate A and to the C terminus of merozoite surface protein 1 correlate with reduced placental malaria in Cameroonian women.Infect Immun. 2004 Mar;72(3):1603-7. doi: 10.1128/IAI.72.3.1603-1607.2004.
• [24] Proto-oncogene c-mpl is involved in spontaneous megakaryocytopoiesis in myeloproliferative disorders.Br J Haematol. 1996 Jan;92(1):60-6. doi: 10.1046/j.1365-2141.1996.00297.x.
• [25] Risk factors of cardiac surgery-associated acute kidney injury: development and validation of a perioperative predictive nomogram.J Nephrol. 2019 Dec;32(6):937-945. doi: 10.1007/s40620-019-00624-z. Epub 2019 Jun 26.
• [26] Cockayne syndrome group A and B proteins converge on transcription-linked resolution of non-B DNA.Proc Natl Acad Sci U S A. 2016 Nov 1;113(44):12502-12507. doi: 10.1073/pnas.1610198113. Epub 2016 Oct 18.
• [27] Cockayne syndrome protein A is a transcription factor of RNA polymerase I and stimulates ribosomal biogenesis and growth.Cell Cycle. 2014;13(13):2029-37. doi: 10.4161/cc.29018. Epub 2014 Apr 29.
• [28] Genome-wide association study of schizophrenia in Ashkenazi Jews.Am J Med Genet B Neuropsychiatr Genet. 2015 Dec;168(8):649-59. doi: 10.1002/ajmg.b.32349. Epub 2015 Jul 21.
• [29] 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.
• [30] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [31] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [32] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [33] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [34] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [35] Changes in gene expressions elicited by physiological concentrations of genistein on human endometrial cancer cells. Mol Carcinog. 2006 Oct;45(10):752-63.
• [36] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.