Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJC7QPQ)

• DOT Name: E3 ubiquitin-protein ligase FANCL (FANCL)
• Synonyms: EC 2.3.2.27; Fanconi anemia group L protein; Fanconi anemia-associated polypeptide of 43 kDa; FAAP43; RING-type E3 ubiquitin transferase FANCL
• Gene Name: FANCL
• Related Disease:
  Fanconi anemia complementation group L
  Male breast carcinoma
  Acute leukaemia
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Advanced cancer
  Fanconi anemia complementation group D2
  Head-neck squamous cell carcinoma
  Leukemia
  Lung neoplasm
  Myelodysplastic syndrome
  Pancytopenia
  Breast cancer
  Breast carcinoma
  Hereditary breast carcinoma
  Neuroblastoma
  Fanconi's anemia
  Childhood acute lymphoblastic leukemia
  Acute lymphocytic leukaemia
  Fanconi anemia complementation group A
• UniProt ID: FANCL_HUMAN
• PDB ID: 3ZQS; 4CCG; 7KZP; 7KZQ; 7KZR; 7KZS; 7KZT; 7KZV
• EC Number: 2.3.2.27
• Pfam ID: PF11793 ; PF09765 ; PF18890 ; PF18891
• Sequence:
  MAVTEASLLRQCPLLLPQNRSKTVYEGFISAQGRDFHLRIVLPEDLQLKNARLLCSWQLR
  TILSGYHRIVQQRMQHSPDLMSFMMELKMLLEVALKNRQELYALPPPPQFYSSLIEEIGT
  LGWDKLVYADTCFSTIKLKAEDASGREHLITLKLKAKYPAESPDYFVDFPVPFCASWTPQ
  SSLISIYSQFLAAIESLKAFWDVMDEIDEKTWVLEPEKPPRSATARRIALGNNVSINIEV
  DPRHPTMLPECFFLGADHVVKPLGIKLSRNIHLWDPENSVLQNLKDVLEIDFPARAILEK
  SDFTMDCGICYAYQLDGTIPDQVCDNSQCGQPFHQICLYEWLRGLLTSRQSFNIIFGECP
  YCSKPITLKMSGRKH
• Function: Ubiquitin ligase protein that mediates monoubiquitination of FANCD2 in the presence of UBE2T, a key step in the DNA damage pathway. Also mediates monoubiquitination of FANCI. May stimulate the ubiquitin release from UBE2W. May be required for proper primordial germ cell proliferation in the embryonic stage, whereas it is probably not needed for spermatogonial proliferation after birth.
• KEGG Pathway:
  Fanconi anemia pathway (hsa03460)
  Ubiquitin mediated proteolysis (hsa04120)
• Reactome Pathway:
  PKR-mediated signaling (R-HSA-9833482)
  Fanconi Anemia Pathway (R-HSA-6783310)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Fanconi anemia complementation group L	DISEU691	Definitive	Autosomal recessive	[1]
Male breast carcinoma	DISUNQ2Q	Definitive	Genetic Variation	[2]
Acute leukaemia	DISDQFDI	Strong	Posttranslational Modification	[3]
Acute monocytic leukemia	DIS28NEL	Strong	Biomarker	[4]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[4]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[5]
Fanconi anemia complementation group D2	DISC76W3	Strong	Altered Expression	[6]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[7]
Leukemia	DISNAKFL	Strong	Genetic Variation	[3]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[8]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[4]
Pancytopenia	DISVKEHV	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	moderate	Genetic Variation	[9]
Breast carcinoma	DIS2UE88	moderate	Genetic Variation	[9]
Hereditary breast carcinoma	DISAEZT5	moderate	Biomarker	[10]
Neuroblastoma	DISVZBI4	moderate	Genetic Variation	[11]
Fanconi's anemia	DISGW6Q8	Supportive	Autosomal recessive	[12]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Disputed	Genetic Variation	[13]
Acute lymphocytic leukaemia	DISPX75S	Limited	Genetic Variation	[13]
Fanconi anemia complementation group A	DIS8PZLI	Limited	Genetic Variation	[14]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	E3 ubiquitin-protein ligase FANCL (FANCL) affects the response to substance of Paclitaxel.	[29]
Topotecan	DMP6G8T	Approved	E3 ubiquitin-protein ligase FANCL (FANCL) affects the response to substance of Topotecan.	[29]
Vinblastine	DM5TVS3	Approved	E3 ubiquitin-protein ligase FANCL (FANCL) affects the response to substance of Vinblastine.	[29]

16 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 E3 ubiquitin-protein ligase FANCL (FANCL).	[15]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of E3 ubiquitin-protein ligase FANCL (FANCL).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of E3 ubiquitin-protein ligase FANCL (FANCL).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase FANCL (FANCL).	[18]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of E3 ubiquitin-protein ligase FANCL (FANCL).	[19]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of E3 ubiquitin-protein ligase FANCL (FANCL).	[20]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of E3 ubiquitin-protein ligase FANCL (FANCL).	[21]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of E3 ubiquitin-protein ligase FANCL (FANCL).	[20]
Piroxicam	DMTK234	Approved	Piroxicam increases the expression of E3 ubiquitin-protein ligase FANCL (FANCL).	[22]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of E3 ubiquitin-protein ligase FANCL (FANCL).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of E3 ubiquitin-protein ligase FANCL (FANCL).	[16]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of E3 ubiquitin-protein ligase FANCL (FANCL).	[24]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of E3 ubiquitin-protein ligase FANCL (FANCL).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of E3 ubiquitin-protein ligase FANCL (FANCL).	[26]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of E3 ubiquitin-protein ligase FANCL (FANCL).	[27]
Resorcinol	DMM37C0	Investigative	Resorcinol increases the expression of E3 ubiquitin-protein ligase FANCL (FANCL).	[28]

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 deleterious mutations in genes other than BRCA2 are infrequent in male breast cancer.Breast Cancer Res Treat. 2018 May;169(1):105-113. doi: 10.1007/s10549-018-4661-x. Epub 2018 Jan 15.
• [3] Hypermethylation of the FANCC and FANCL promoter regions in sporadic acute leukaemia.Cell Oncol. 2008;30(4):299-306. doi: 10.3233/clo-2008-0426.
• [4] Germline Genetic Predisposition to Hematologic Malignancy.J Clin Oncol. 2017 Mar 20;35(9):1018-1028. doi: 10.1200/JCO.2016.70.8644. Epub 2017 Feb 13.
• [5] Multigene panel testing beyond BRCA1/2 in breast/ovarian cancer Spanish families and clinical actionability of findings.J Cancer Res Clin Oncol. 2018 Dec;144(12):2495-2513. doi: 10.1007/s00432-018-2763-9. Epub 2018 Oct 10.
• [6] Constitutive role of the Fanconi anemia D2 gene in the replication stress response.J Biol Chem. 2017 Dec 8;292(49):20184-20195. doi: 10.1074/jbc.M117.814780. Epub 2017 Oct 11.
• [7] Assessing the spectrum of germline variation in Fanconi anemia genes among patients with head and neck carcinoma before age 50.Cancer. 2017 Oct 15;123(20):3943-3954. doi: 10.1002/cncr.30802. Epub 2017 Jul 5.
• [8] Altered expression of FANCL confers mitomycin C sensitivity in Calu-6 lung cancer cells.Cancer Biol Ther. 2006 Dec;5(12):1632-6. doi: 10.4161/cbt.5.12.3351. Epub 2006 Dec 5.
• [9] Hereditary truncating mutations of DNA repair and other genes in BRCA1/BRCA2/PALB2-negatively tested breast cancer patients.Clin Genet. 2016 Oct;90(4):324-33. doi: 10.1111/cge.12748. Epub 2016 Mar 4.
• [10] Mutational analysis of FANCL, FANCM and the recently identified FANCI suggests that among the 13 known Fanconi Anemia genes, only FANCD1/BRCA2 plays a major role in high-risk breast cancer predisposition.Carcinogenesis. 2009 Nov;30(11):1898-902. doi: 10.1093/carcin/bgp218. Epub 2009 Sep 8.
• [11] Natural history and biology of stage A neuroblastoma: a Pediatric Oncology Group Study.J Pediatr Hematol Oncol. 2000 May-Jun;22(3):197-205. doi: 10.1097/00043426-200005000-00003.
• [12] Fanconi Anemia. 2002 Feb 14 [updated 2021 Jun 3]. 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.
• [13] Genome-wide analysis links NFATC2 with asparaginase hypersensitivity.Blood. 2015 Jul 2;126(1):69-75. doi: 10.1182/blood-2015-02-628800. Epub 2015 May 18.
• [14] A founder variant in the South Asian population leads to a high prevalence of FANCL Fanconi anemia cases in India.Hum Mutat. 2020 Jan;41(1):122-128. doi: 10.1002/humu.23914. Epub 2019 Sep 26.
• [15] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [16] 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.
• [17] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [18] 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.
• [19] 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.
• [20] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [21] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [22] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [23] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [24] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [25] 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.
• [26] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [27] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [28] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [29] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.