Details of Drug Off-Target (DOT)

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

• DOT Name: ATP-dependent DNA helicase PIF1 (PIF1)
• Synonyms: EC 3.6.4.12; DNA repair and recombination helicase PIF1; PIF1/RRM3 DNA helicase-like protein
• Gene Name: PIF1
• Related Disease:
  Neoplasm
  Cerebral palsy
  Congestive heart failure
  Epileptic encephalopathy
  Fatty liver disease
  Isolated cleft palate
  Prostate cancer
  Prostate carcinoma
  X-linked Opitz G/BBB syndrome
  Hereditary breast carcinoma
  Dental caries
• UniProt ID: PIF1_HUMAN
• PDB ID: 5FHH; 6HPH; 6HPQ; 6HPT; 6HPU
• EC Number: 3.6.4.12
• Pfam ID: PF05970 ; PF21530
• Sequence:
  MLSGIEAAAGEYEDSELRCRVAVEELSPGGQPRRRQALRTAELSLGRNERRELMLRLQAP
  GPAGRPRCFPLRAARLFTRFAEAGRSTLRLPAHDTPGAGAVQLLLSDCPPDRLRRFLRTL
  RLKLAAAPGPGPASARAQLLGPRPRDFVTISPVQPEERRLRAATRVPDTTLVKRPVEPQA
  GAEPSTEAPRWPLPVKRLSLPSTKPQLSEEQAAVLRAVLKGQSIFFTGSAGTGKSYLLKR
  ILGSLPPTGTVATASTGVAACHIGGTTLHAFAGIGSGQAPLAQCVALAQRPGVRQGWLNC
  QRLVIDEISMVEADLFDKLEAVARAVRQQNKPFGGIQLIICGDFLQLPPVTKGSQPPRFC
  FQSKSWKRCVPVTLELTKVWRQADQTFISLLQAVRLGRCSDEVTRQLQATASHKVGRDGI
  VATRLCTHQDDVALTNERRLQELPGKVHRFEAMDSNPELASTLDAQCPVSQLLQLKLGAQ
  VMLVKNLSVSRGLVNGARGVVVGFEAEGRGLPQVRFLCGVTEVIHADRWTVQATGGQLLS
  RQQLPLQLAWAMSIHKSQGMTLDCVEISLGRVFASGQAYVALSRARSLQGLRVLDFDPMA
  VRCDPRVLHFYATLRRGRSLSLESPDDDEAASDQENMDPIL
• Function: DNA-dependent ATPase and 5'-3' DNA helicase required for the maintenance of both mitochondrial and nuclear genome stability. Efficiently unwinds G-quadruplex (G4) DNA structures and forked RNA-DNA hybrids. Resolves G4 structures, preventing replication pausing and double-strand breaks (DSBs) at G4 motifs. Involved in the maintenance of telomeric DNA. Inhibits telomere elongation, de novo telomere formation and telomere addition to DSBs via catalytic inhibition of telomerase. Reduces the processivity of telomerase by displacing active telomerase from DNA ends. Releases telomerase by unwinding the short telomerase RNA/telomeric DNA hybrid that is the intermediate in the telomerase reaction. Possesses an intrinsic strand annealing activity.
• Tissue Specificity: Weak ubiquitous expression.
• Reactome Pathway: Telomere Extension By Telomerase (R-HSA-171319)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Cerebral palsy	DIS82ODL	Strong	Biomarker	[2]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[3]
Epileptic encephalopathy	DISZOCA3	Strong	Biomarker	[4]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[5]
Isolated cleft palate	DISV80CD	Strong	Biomarker	[2]
Prostate cancer	DISF190Y	Strong	Biomarker	[6]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[6]
X-linked Opitz G/BBB syndrome	DISQ14EC	Strong	Biomarker	[4]
Hereditary breast carcinoma	DISAEZT5	moderate	Biomarker	[7]
Dental caries	DISRBCMD	Limited	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Gemcitabine	DMSE3I7	Approved	ATP-dependent DNA helicase PIF1 (PIF1) decreases the response to substance of Gemcitabine.	[24]

15 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 ATP-dependent DNA helicase PIF1 (PIF1).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of ATP-dependent DNA helicase PIF1 (PIF1).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of ATP-dependent DNA helicase PIF1 (PIF1).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of ATP-dependent DNA helicase PIF1 (PIF1).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of ATP-dependent DNA helicase PIF1 (PIF1).	[13]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of ATP-dependent DNA helicase PIF1 (PIF1).	[14]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of ATP-dependent DNA helicase PIF1 (PIF1).	[15]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of ATP-dependent DNA helicase PIF1 (PIF1).	[16]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of ATP-dependent DNA helicase PIF1 (PIF1).	[17]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of ATP-dependent DNA helicase PIF1 (PIF1).	[17]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of ATP-dependent DNA helicase PIF1 (PIF1).	[18]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of ATP-dependent DNA helicase PIF1 (PIF1).	[19]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of ATP-dependent DNA helicase PIF1 (PIF1).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of ATP-dependent DNA helicase PIF1 (PIF1).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of ATP-dependent DNA helicase PIF1 (PIF1).	[23]

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 ATP-dependent DNA helicase PIF1 (PIF1).	[20]

References

• [1] Human PIF1 helicase supports DNA replication and cell growth under oncogenic-stress.Oncotarget. 2014 Nov 30;5(22):11381-98. doi: 10.18632/oncotarget.2501.
• [2] Proteolysis-inducing factor core peptide mediates dermcidin-induced proliferation of hepatic cells through multiple signalling networks.Int J Oncol. 2011 Sep;39(3):709-18. doi: 10.3892/ijo.2011.1064. Epub 2011 Jun 3.
• [3] Is there a human homologue to the murine proteolysis-inducing factor?.Clin Cancer Res. 2007 Sep 1;13(17):4984-92. doi: 10.1158/1078-0432.CCR-07-0946.
• [4] In vitro production of Spodoptera exigua multiple nucleopolyhedrovirus with enhanced insecticidal activity using a genotypically defined virus inoculum.J Biotechnol. 2017 Oct 10;259:19-25. doi: 10.1016/j.jbiotec.2017.08.001. Epub 2017 Aug 2.
• [5] Petite Integration Factor 1 (PIF1) helicase deficiency increases weight gain in Western diet-fed female mice without increased inflammatory markers or decreased glucose clearance.PLoS One. 2019 May 28;14(5):e0203101. doi: 10.1371/journal.pone.0203101. eCollection 2019.
• [6] Dermcidin expression confers a survival advantage in prostate cancer cells subjected to oxidative stress or hypoxia.Prostate. 2007 Sep 1;67(12):1308-17. doi: 10.1002/pros.20618.
• [7] The functions of the multi-tasking Pfh1(Pif1) helicase.Curr Genet. 2017 Aug;63(4):621-626. doi: 10.1007/s00294-016-0675-2. Epub 2017 Jan 4.
• [8] Genetic- and Lifestyle-dependent Dental Caries Defined by the Acidic Proline-rich Protein Genes PRH1 and PRH2.EBioMedicine. 2017 Dec;26:38-46. doi: 10.1016/j.ebiom.2017.11.019. Epub 2017 Nov 22.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [11] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [12] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [13] 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.
• [14] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [15] 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.
• [16] 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.
• [17] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [18] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [19] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [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] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [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] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [24] Petite Integration Factor 1 knockdown enhances gemcitabine sensitivity in pancreatic cancer cells via increasing DNA damage. J Appl Toxicol. 2023 Oct;43(10):1522-1532. doi: 10.1002/jat.4494. Epub 2023 May 16.