Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1LM1HZ)

• DOT Name: Fanconi-associated nuclease 1 (FAN1)
• Synonyms: EC 3.1.21.-; EC 3.1.4.1; FANCD2/FANCI-associated nuclease 1; hFAN1; Myotubularin-related protein 15
• Gene Name: FAN1
• Related Disease:
  Interstitial nephritis
  Autism
  Autism spectrum disorder
  Breast cancer
  Breast carcinoma
  Cardiac arrest
  Cerebellar ataxia
  Chronic kidney disease
  Colorectal carcinoma
  Cystic kidney disease
  Huntington disease
  Karyomegalic interstitial nephritis
  Neoplasm
  Renal fibrosis
  Lynch syndrome
  Hereditary nonpolyposis colon cancer
  Lynch syndrome 1
  Lynch syndrome 2
  Schizophrenia
• UniProt ID: FAN1_HUMAN
• PDB ID: 4REA; 4REB; 4REC; 4RI8; 4RI9; 4RIA; 4RIB; 4RIC; 4RID; 4RY3
• EC Number: 3.1.21.-; 3.1.4.1
• Pfam ID: PF21315 ; PF21169 ; PF21170 ; PF08774
• Sequence:
  MMSEGKPPDKKRPRRSLSISKNKKKASNSIISCFNNAPPAKLACPVCSKMVPRYDLNRHL
  DEMCANNDFVQVDPGQVGLINSNVSMVDLTSVTLEDVTPKKSPPPKTNLTPGQSDSAKRE
  VKQKISPYFKSNDVVCKNQDELRNRSVKVICLGSLASKLSRKYVKAKKSIDKDEEFAGSS
  PQSSKSTVVKSLIDNSSEIEDEDQILENSSQKENVFKCDSLKEECIPEHMVRGSKIMEAE
  SQKATRECEKSALTPGFSDNAIMLFSPDFTLRNTLKSTSEDSLVKQECIKEVVEKREACH
  CEEVKMTVASEAKIQLSDSEAKSHSSADDASAWSNIQEAPLQDDSCLNNDIPHSIPLEQG
  SSCNGPGQTTGHPYYLRSFLVVLKTVLENEDDMLLFDEQEKGIVTKFYQLSATGQKLYVR
  LFQRKLSWIKMTKLEYEEIALDLTPVIEELTNAGFLQTESELQELSEVLELLSAPELKSL
  AKTFHLVNPNGQKQQLVDAFLKLAKQRSVCTWGKNKPGIGAVILKRAKALAGQSVRICKG
  PRAVFSRILLLFSLTDSMEDEDAACGGQGQLSTVLLVNLGRMEFPSYTINRKTHIFQDRD
  DLIRYAAATHMLSDISSAMANGNWEEAKELAQCAKRDWNRLKNHPSLRCHEDLPLFLRCF
  TVGWIYTRILSRFVEILQRLHMYEEAVRELESLLSQRIYCPDSRGRWWDRLALNLHQHLK
  RLEPTIKCITEGLADPEVRTGHRLSLYQRAVRLRESPSCKKFKHLFQQLPEMAVQDVKHV
  TITGRLCPQRGMCKSVFVMEAGEAADPTTVLCSVEELALAHYRRSGFDQGIHGEGSTFST
  LYGLLLWDIIFMDGIPDVFRNACQAFPLDLCTDSFFTSRRPALEARLQLIHDAPEESLRA
  WVAATWHEQEGRVASLVSWDRFTSLQQAQDLVSCLGGPVLSGVCRHLAADFRHCRGGLPD
  LVVWNSQSRHFKLVEVKGPNDRLSHKQMIWLAELQKLGAEVEVCHVVAVGAKSQSLS
• Function: Nuclease required for the repair of DNA interstrand cross-links (ICL) recruited at sites of DNA damage by monoubiquitinated FANCD2. Specifically involved in repair of ICL-induced DNA breaks by being required for efficient homologous recombination, probably in the resolution of homologous recombination intermediates. Not involved in DNA double-strand breaks resection. Acts as a 5'-3' exonuclease that anchors at a cut end of DNA and cleaves DNA successively at every third nucleotide, allowing to excise an ICL from one strand through flanking incisions. Probably keeps excising with 3'-flap annealing until it reaches and unhooks the ICL. Acts at sites that have a 5'-terminal phosphate anchor at a nick or a 1- or 2-nucleotide flap and is augmented by a 3' flap. Also has endonuclease activity toward 5'-flaps.
• KEGG Pathway: Fanconi anemia pathway (hsa03460)
• Reactome Pathway: Fanconi Anemia Pathway (R-HSA-6783310)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Interstitial nephritis	DISKQGND	Definitive	Genetic Variation	[1]
Autism	DISV4V1Z	Strong	Biomarker	[2]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Cardiac arrest	DIS9DIA4	Strong	Genetic Variation	[4]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[5]
Chronic kidney disease	DISW82R7	Strong	Genetic Variation	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[6]
Cystic kidney disease	DISRT1LM	Strong	Biomarker	[7]
Huntington disease	DISQPLA4	Strong	Genetic Variation	[5]
Karyomegalic interstitial nephritis	DISY3YH1	Strong	Autosomal recessive	[8]
Neoplasm	DISZKGEW	Strong	Biomarker	[9]
Renal fibrosis	DISMHI3I	Strong	Genetic Variation	[7]
Lynch syndrome	DIS3IW5F	Supportive	Autosomal dominant	[10]
Hereditary nonpolyposis colon cancer	DISPA49R	Limited	Autosomal dominant	[11]
Lynch syndrome 1	DISSABLZ	Limited	Biomarker	[12]
Lynch syndrome 2	DISRLYU1	Limited	Biomarker	[12]
Schizophrenia	DISSRV2N	Limited	Biomarker	[13]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Fanconi-associated nuclease 1 (FAN1) decreases the response to substance of Cisplatin.	[27]
Mitomycin	DMH0ZJE	Approved	Fanconi-associated nuclease 1 (FAN1) increases the response to substance of Mitomycin.	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Fanconi-associated nuclease 1 (FAN1).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Fanconi-associated nuclease 1 (FAN1).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Fanconi-associated nuclease 1 (FAN1).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Fanconi-associated nuclease 1 (FAN1).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Fanconi-associated nuclease 1 (FAN1).	[18]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Fanconi-associated nuclease 1 (FAN1).	[19]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Fanconi-associated nuclease 1 (FAN1).	[20]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Fanconi-associated nuclease 1 (FAN1).	[21]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Fanconi-associated nuclease 1 (FAN1).	[22]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Fanconi-associated nuclease 1 (FAN1).	[23]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Fanconi-associated nuclease 1 (FAN1).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Fanconi-associated nuclease 1 (FAN1).	[26]

1 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 decreases the methylation of Fanconi-associated nuclease 1 (FAN1).	[25]

References

• [1] Karyomegalic Interstitial Nephritis: A Case Report and Review of the Literature.Medicine (Baltimore). 2016 May;95(20):e3349. doi: 10.1097/MD.0000000000003349.
• [2] Scan statistic-based analysis of exome sequencing data identifies FAN1 at 15q13.3 as a susceptibility gene for schizophrenia and autism.Proc Natl Acad Sci U S A. 2014 Jan 7;111(1):343-8. doi: 10.1073/pnas.1309475110. Epub 2013 Dec 16.
• [3] FAN1 variants identified in multiple-case early-onset breast cancer families via exome sequencing: no evidence for association with risk for breast cancer.Breast Cancer Res Treat. 2011 Dec;130(3):1043-9. doi: 10.1007/s10549-011-1704-y. Epub 2011 Aug 21.
• [4] DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases.Ann Neurol. 2016 Jun;79(6):983-90. doi: 10.1002/ana.24656. Epub 2016 May 6.
• [5] Variation in DNA Repair System Gene as an Additional Modifier of Age at Onset in Spinocerebellar Ataxia Type 3/Machado-Joseph Disease.Neuromolecular Med. 2020 Mar;22(1):133-138. doi: 10.1007/s12017-019-08572-4. Epub 2019 Oct 5.
• [6] Validation of Recently Proposed Colorectal Cancer Susceptibility Gene Variants in an Analysis of Families and Patients-a Systematic Review.Gastroenterology. 2017 Jan;152(1):75-77.e4. doi: 10.1053/j.gastro.2016.09.041. Epub 2016 Oct 3.
• [7] FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair. Nat Genet. 2012 Jul 8;44(8):910-5. doi: 10.1038/ng.2347.
• [8] Karyomegalic nephropathy: an uncommon cause of progressive renal failure. Nephrol Dial Transplant. 2002 Nov;17(11):1914-20. doi: 10.1093/ndt/17.11.1914.
• [9] FAN1 interaction with ubiquitylated PCNA alleviates replication stress and preserves genomic integrity independently of BRCA2.Nat Commun. 2017 Oct 20;8(1):1073. doi: 10.1038/s41467-017-01074-6.
• [10] Germline Mutations in FAN1 Cause Hereditary Colorectal Cancer by Impairing DNA Repair. Gastroenterology. 2015 Sep;149(3):563-6. doi: 10.1053/j.gastro.2015.05.056. Epub 2015 Jun 5.
• [11] 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.
• [12] Ubiquitinated Fancd2 recruits Fan1 to stalled replication forks to prevent genome instability.Science. 2016 Feb 19;351(6275):846-9. doi: 10.1126/science.aad5634. Epub 2016 Jan 21.
• [13] A pilot study on commonality and specificity of copy number variants in schizophrenia and bipolar disorder.Transl Psychiatry. 2016 May 31;6(5):e824. doi: 10.1038/tp.2016.96.
• [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] 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.
• [16] 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.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [20] Hypoxia-inducible factor-1 (HIF-1) pathway activation by quercetin in human lens epithelial cells. Exp Eye Res. 2009 Dec;89(6):995-1002. doi: 10.1016/j.exer.2009.08.011. Epub 2009 Sep 1.
• [21] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [22] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [23] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [24] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [25] 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.
• [26] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [27] KIAA1018/FAN1 nuclease protects cells against genomic instability induced by interstrand cross-linking agents. Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21553-7. doi: 10.1073/pnas.1011081107. Epub 2010 Nov 29.
• [28] FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair. Nat Genet. 2012 Jul 8;44(8):910-5. doi: 10.1038/ng.2347.