Details of Drug Off-Target (DOT)

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

• DOT Name: Serine protease FAM111A (FAM111A)
• Synonyms: EC 3.4.21.-
• Gene Name: FAM111A
• Related Disease:
  Autosomal dominant Kenny-Caffey syndrome
  Autosomal recessive Kenny-Caffey syndrome
  Intellectual disability
  Kenny-Caffey syndrome
  Osteocraniostenosis
  Xerophthalmia
  Hypoparathyroidism
• UniProt ID: F111A_HUMAN
• EC Number: 3.4.21.-
• Pfam ID: PF13365
• Sequence:
  MSCKKQRSRKHSVNEKCNMKIEHYFSPVSKEQQNNCSTSLMRMESRGDPRATTNTQAQRF
  HSPKKNPEDQTMPQNRTIYVTLKVNHRRNQDMKLKLTHSENSSLYMALNTLQAVRKEIET
  HQGQEMLVRGTEGIKEYINLGMPLSCFPEGGQVVITFSQSKSKQKEDNHIFGRQDKASTE
  CVKFYIHAIGIGKCKRRIVKCGKLHKKGRKLCVYAFKGETIKDALCKDGRFLSFLENDDW
  KLIENNDTILESTQPVDELEGRYFQVEVEKRMVPSAAASQNPESEKRNTCVLREQIVAQY
  PSLKRESEKIIENFKKKMKVKNGETLFELHRTTFGKVTKNSSSIKVVKLLVRLSDSVGYL
  FWDSATTGYATCFVFKGLFILTCRHVIDSIVGDGIEPSKWATIIGQCVRVTFGYEELKDK
  ETNYFFVEPWFEIHNEELDYAVLKLKENGQQVPMELYNGITPVPLSGLIHIIGHPYGEKK
  QIDACAVIPQGQRAKKCQERVQSKKAESPEYVHMYTQRSFQKIVHNPDVITYDTEFFFGA
  SGSPVFDSKGSLVAMHAAGFAYTYQNETRSIIEFGSTMESILLDIKQRHKPWYEEVFVNQ
  QDVEMMSDEDL
• Function: Single-stranded DNA-binding serine protease that mediates the proteolytic cleavage of covalent DNA-protein cross-links (DPCs) during DNA synthesis, thereby playing a key role in maintaining genomic integrity. DPCs are highly toxic DNA lesions that interfere with essential chromatin transactions, such as replication and transcription, and which are induced by reactive agents, such as UV light or formaldehyde. Protects replication fork from stalling by removing DPCs, such as covalently trapped topoisomerase 1 (TOP1) adducts on DNA lesion, or poly(ADP-ribose) polymerase 1 (PARP1)-DNA complexes trapped by PARP inhibitors. Required for PCNA loading on replication sites. Promotes S-phase entry and DNA synthesis. Acts also as a restriction factor for some viruses including SV40 polyomavirus and vaccinia virus. Mechanistically, affects nuclear barrier function during viral replication by mediating the disruption of the nuclear pore complex (NPC) via its protease activity. In turn, interacts with vaccinia virus DNA-binding protein OPG079 in the cytoplasm and promotes its degradation without the need of its protease activity but through autophagy.

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant Kenny-Caffey syndrome	DISBSFV8	Definitive	Autosomal dominant	[1]
Autosomal recessive Kenny-Caffey syndrome	DISN3BL7	Strong	Genetic Variation	[2]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[2]
Kenny-Caffey syndrome	DISEL08B	Strong	Genetic Variation	[3]
Osteocraniostenosis	DISO1IT9	Strong	Autosomal dominant	[1]
Xerophthalmia	DIS5B72B	Strong	Genetic Variation	[2]
Hypoparathyroidism	DISICS0V	moderate	Genetic Variation	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Topotecan	DMP6G8T	Approved	Serine protease FAM111A (FAM111A) affects the response to substance of Topotecan.	[25]

22 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 Serine protease FAM111A (FAM111A).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Serine protease FAM111A (FAM111A).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Serine protease FAM111A (FAM111A).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Serine protease FAM111A (FAM111A).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Serine protease FAM111A (FAM111A).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Serine protease FAM111A (FAM111A).	[9]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Serine protease FAM111A (FAM111A).	[10]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Serine protease FAM111A (FAM111A).	[11]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Serine protease FAM111A (FAM111A).	[12]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Serine protease FAM111A (FAM111A).	[13]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Serine protease FAM111A (FAM111A).	[14]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the expression of Serine protease FAM111A (FAM111A).	[10]
Piroxicam	DMTK234	Approved	Piroxicam increases the expression of Serine protease FAM111A (FAM111A).	[15]
Palbociclib	DMD7L94	Approved	Palbociclib decreases the expression of Serine protease FAM111A (FAM111A).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Serine protease FAM111A (FAM111A).	[17]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Serine protease FAM111A (FAM111A).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Serine protease FAM111A (FAM111A).	[19]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Serine protease FAM111A (FAM111A).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Serine protease FAM111A (FAM111A).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Serine protease FAM111A (FAM111A).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Serine protease FAM111A (FAM111A).	[13]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Serine protease FAM111A (FAM111A).	[24]

2 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 Serine protease FAM111A (FAM111A).	[18]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Serine protease FAM111A (FAM111A).	[21]

References

• [1] FAM111A mutations result in hypoparathyroidism and impaired skeletal development. Am J Hum Genet. 2013 Jun 6;92(6):990-5. doi: 10.1016/j.ajhg.2013.04.020. Epub 2013 May 16.
• [2] A recurrent de novo FAM111A mutation causes Kenny-Caffey syndrome type 2.J Bone Miner Res. 2014 Apr;29(4):992-8. doi: 10.1002/jbmr.2091.
• [3] Contribution of DNA Replication to the FAM111A-Mediated Simian Virus 40 Host Range Phenotype.J Virol. 2018 Dec 10;93(1):e01330-18. doi: 10.1128/JVI.01330-18. Print 2019 Jan 1.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] 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.
• [10] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [11] 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.
• [12] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [15] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [16] Cdk4/6 inhibition induces epithelial-mesenchymal transition and enhances invasiveness in pancreatic cancer cells. Mol Cancer Ther. 2012 Oct;11(10):2138-48. doi: 10.1158/1535-7163.MCT-12-0562. Epub 2012 Aug 6.
• [17] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [18] 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.
• [19] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [20] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [25] 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.