Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT01D5CE)

• DOT Name: DNA-dependent metalloprotease SPRTN (SPRTN)
• Synonyms: EC 3.4.24.-; DNA damage protein targeting VCP; DVC1; Protein with SprT-like domain at the N terminus; Spartan
• Gene Name: SPRTN
• Related Disease:
  Hutchinson-Gilford progeria syndrome
  Acute myocardial infarction
  Advanced cancer
  Castration-resistant prostate carcinoma
  Exanthem
  Migraine disorder
  Peripheral arterial disease
  Peripheral vascular disease
  Premature aging syndrome
  Progeroid features-hepatocellular carcinoma predisposition syndrome
  Carcinoma of liver and intrahepatic biliary tract
  Cockayne syndrome
  Hepatocellular carcinoma
  Liver cancer
  Marfan syndrome
  Metastatic malignant neoplasm
• UniProt ID: SPRTN_HUMAN
• PDB ID: 5IY4; 6MDW; 6MDX
• EC Number: 3.4.24.-
• Pfam ID: PF10263
• Sequence:
  MDDDLMLALRLQEEWNLQEAERDHAQESLSLVDASWELVDPTPDLQALFVQFNDQFFWGQ
  LEAVEVKWSVRMTLCAGICSYEGKGGMCSIRLSEPLLKLRPRKDLVETLLHEMIHAYLFV
  TNNDKDREGHGPEFCKHMHRINSLTGANITVYHTFHDEVDEYRRHWWRCNGPCQHRPPYY
  GYVKRATNREPSAHDYWWAEHQKTCGGTYIKIKEPENYSKKGKGKAKLGKEPVLAAENKD
  KPNRGEAQLVIPFSGKGYVLGETSNLPSPGKLITSHAINKTQDLLNQNHSANAVRPNSKI
  KVKFEQNGSSKNSHLVSPAVSNSHQNVLSNYFPRVSFANQKAFRGVNGSPRISVTVGNIP
  KNSVSSSSQRRVSSSKISLRNSSKVTESASVMPSQDVSGSEDTFPNKRPRLEDKTVFDNF
  FIKKEQIKSSGNDPKYSTTTAQNSSSSSSQSKMVNCPVCQNEVLESQINEHLDWCLEGDS
  IKVKSEESL
• Function: DNA-dependent metalloendopeptidase 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. Associates with the DNA replication machinery and specifically removes DPCs during DNA synthesis. Catalyzes proteolytic cleavage of the HMCES DNA-protein cross-link following unfolding by the BRIP1/FANCJ helicase. Acts as a pleiotropic protease for DNA-binding proteins cross-linked with DNA, such as TOP1, TOP2A, histones H3 and H4. Mediates degradation of DPCs that are not ubiquitinated, while it is not able to degrade ubiquitinated DPCs. SPRTN activation requires polymerase collision with DPCs followed by helicase bypass of DPCs. Involved in recruitment of VCP/p97 to sites of DNA damage. Also acts as an activator of CHEK1 during normal DNA replication by mediating proteolytic cleavage of CHEK1, thereby promoting CHEK1 removal from chromatin and subsequent activation. Does not activate CHEK1 in response to DNA damage. May also act as a 'reader' of ubiquitinated PCNA: recruited to sites of UV damage and interacts with ubiquitinated PCNA and RAD18, the E3 ubiquitin ligase that monoubiquitinates PCNA. Facilitates chromatin association of RAD18 and is required for efficient PCNA monoubiquitination, promoting a feed-forward loop to enhance PCNA ubiquitination and translesion DNA synthesis.
• Reactome Pathway: Translesion Synthesis by POLH (R-HSA-110320)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hutchinson-Gilford progeria syndrome	DISY55BU	Definitive	Biomarker	[1]
Acute myocardial infarction	DISE3HTG	Strong	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Castration-resistant prostate carcinoma	DISVGAE6	Strong	Biomarker	[4]
Exanthem	DISAFOQN	Strong	Genetic Variation	[5]
Migraine disorder	DISFCQTG	Strong	Biomarker	[6]
Peripheral arterial disease	DIS78WFB	Strong	Genetic Variation	[7]
Peripheral vascular disease	DISXSU1Y	Strong	Biomarker	[7]
Premature aging syndrome	DIS51AGT	Strong	Biomarker	[8]
Progeroid features-hepatocellular carcinoma predisposition syndrome	DISD336E	Moderate	Autosomal recessive	[9]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Biomarker	[8]
Cockayne syndrome	DISW6GL2	Limited	Genetic Variation	[10]
Hepatocellular carcinoma	DIS0J828	Limited	Genetic Variation	[11]
Liver cancer	DISDE4BI	Limited	Biomarker	[8]
Marfan syndrome	DISVEUWZ	Limited	Genetic Variation	[12]
Metastatic malignant neoplasm	DIS86UK6	Limited	Genetic Variation	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of DNA-dependent metalloprotease SPRTN (SPRTN).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of DNA-dependent metalloprotease SPRTN (SPRTN).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DNA-dependent metalloprotease SPRTN (SPRTN).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of DNA-dependent metalloprotease SPRTN (SPRTN).	[17]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of DNA-dependent metalloprotease SPRTN (SPRTN).	[18]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of DNA-dependent metalloprotease SPRTN (SPRTN).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of DNA-dependent metalloprotease SPRTN (SPRTN).	[21]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of DNA-dependent metalloprotease SPRTN (SPRTN).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of DNA-dependent metalloprotease SPRTN (SPRTN).	[23]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of DNA-dependent metalloprotease SPRTN (SPRTN).	[25]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of DNA-dependent metalloprotease SPRTN (SPRTN).	[26]

3 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-dependent metalloprotease SPRTN (SPRTN).	[20]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of DNA-dependent metalloprotease SPRTN (SPRTN).	[24]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of DNA-dependent metalloprotease SPRTN (SPRTN).	[24]

References

• [1] Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features. Nat Genet. 2014 Nov;46(11):1239-44. doi: 10.1038/ng.3103. Epub 2014 Sep 28.
• [2] Tailored Adjunctive Cilostazol Therapy Based on CYP2C19 Genotyping in Patients With Acute Myocardial Infarction- The CALDERA-GENE Study.Circ J. 2018 May 25;82(6):1517-1525. doi: 10.1253/circj.CJ-18-0197. Epub 2018 May 8.
• [3] Metalloprotease SPRTN/DVC1 Orchestrates Replication-Coupled DNA-Protein Crosslink Repair.Mol Cell. 2016 Nov 17;64(4):704-719. doi: 10.1016/j.molcel.2016.09.032. Epub 2016 Oct 27.
• [4] Apalutamide: A new agent in the management of prostate cancer.J Oncol Pharm Pract. 2019 Dec;25(8):1968-1978. doi: 10.1177/1078155219864424. Epub 2019 Jul 30.
• [5] Enzalutamide and Apalutamide: In Vitro Chemical Reactivity Studies and Activity in a Mouse Drug Allergy Model.Chem Res Toxicol. 2020 Jan 21;33(1):211-222. doi: 10.1021/acs.chemrestox.9b00247. Epub 2019 Oct 9.
• [6] Lasmiditan for the acute treatment of migraine: Subgroup analyses by prior response to triptans.Cephalalgia. 2020 Jan;40(1):19-27. doi: 10.1177/0333102419889350. Epub 2019 Nov 19.
• [7] DVC1-0101 to treat peripheral arterial disease: a Phase I/IIa open-label dose-escalation clinical trial. Mol Ther. 2013 Mar;21(3):707-14.
• [8] SPRTN protease and checkpoint kinase 1 cross-activation loop safeguards DNA replication.Nat Commun. 2019 Jul 17;10(1):3142. doi: 10.1038/s41467-019-11095-y.
• [9] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [10] SPRTN is a new player in an old story.Nat Genet. 2014 Nov;46(11):1155-7. doi: 10.1038/ng.3125.
• [11] Spartan deficiency causes accumulation of Topoisomerase 1 cleavage complexes and tumorigenesis.Nucleic Acids Res. 2017 May 5;45(8):4564-4576. doi: 10.1093/nar/gkx107.
• [12] Apalutamid: Eine neue Option fr die Therapie des Hochrisiko-M0CRPC.Oncol Res Treat. 2019;42 Suppl 2:4-6. doi: 10.1159/000496365. Epub 2019 Apr 8.
• [13] Effect of apalutamide on health-related quality of life in patients with non-metastatic castration-resistant prostate cancer: an analysis of the SPARTAN randomised, placebo-controlled, phase 3 trial.Lancet Oncol. 2018 Oct;19(10):1404-1416. doi: 10.1016/S1470-2045(18)30456-X. Epub 2018 Sep 10.
• [14] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [15] 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.
• [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] 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.
• [18] 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.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] 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.
• [21] Synergistic effect of JQ1 and rapamycin for treatment of human osteosarcoma. Int J Cancer. 2015 May 1;136(9):2055-64.
• [22] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [23] 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.
• [24] 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.
• [25] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [26] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.