Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4DJFFU)

• DOT Name: DNA replication ATP-dependent helicase/nuclease DNA2 (DNA2)
• Synonyms: hDNA2; DNA replication ATP-dependent helicase-like homolog
• Gene Name: DNA2
• Related Disease:
  Breast cancer
  Breast carcinoma
  Advanced cancer
  Alzheimer disease
  Bladder cancer
  Bloom syndrome
  Fanconi anemia complementation group A
  Fanconi's anemia
  leukaemia
  Leukemia
  Mitochondrial DNA deletion syndrome with progressive myopathy
  Mitochondrial myopathy
  Myopathy
  Neoplasm
  Ovarian cancer
  Ptosis
  Seckel syndrome 8
  Urinary bladder cancer
  Urinary bladder neoplasm
  Pancreatic cancer
  Werner syndrome
  Li-Fraumeni syndrome
  Hepatitis B virus infection
  Myeloproliferative neoplasm
  Seckel syndrome
• UniProt ID: DNA2_HUMAN
• PDB ID: 5EAY
• EC Number: 3.1.-.-; 3.6.4.12
• Pfam ID: PF13086 ; PF13087 ; PF08696 ; PF21123
• Sequence:
  MEQLNELELLMEKSFWEEAELPAELFQKKVVASFPRTVLSTGMDNRYLVLAVNTVQNKEG
  NCEKRLVITASQSLENKELCILRNDWCSVPVEPGDIIHLEGDCTSDTWIIDKDFGYLILY
  PDMLISGTSIASSIRCMRRAVLSETFRSSDPATRQMLIGTVLHEVFQKAINNSFAPEKLQ
  ELAFQTIQEIRHLKEMYRLNLSQDEIKQEVEDYLPSFCKWAGDFMHKNTSTDFPQMQLSL
  PSDNSKDNSTCNIEVVKPMDIEESIWSPRFGLKGKIDVTVGVKIHRGYKTKYKIMPLELK
  TGKESNSIEHRSQVVLYTLLSQERRADPEAGLLLYLKTGQMYPVPANHLDKRELLKLRNQ
  MAFSLFHRISKSATRQKTQLASLPQIIEEEKTCKYCSQIGNCALYSRAVEQQMDCSSVPI
  VMLPKIEEETQHLKQTHLEYFSLWCLMLTLESQSKDNKKNHQNIWLMPASEMEKSGSCIG
  NLIRMEHVKIVCDGQYLHNFQCKHGAIPVTNLMAGDRVIVSGEERSLFALSRGYVKEINM
  TTVTCLLDRNLSVLPESTLFRLDQEEKNCDIDTPLGNLSKLMENTFVSKKLRDLIIDFRE
  PQFISYLSSVLPHDAKDTVACILKGLNKPQRQAMKKVLLSKDYTLIVGMPGTGKTTTICT
  LVRILYACGFSVLLTSYTHSAVDNILLKLAKFKIGFLRLGQIQKVHPAIQQFTEQEICRS
  KSIKSLALLEELYNSQLIVATTCMGINHPIFSRKIFDFCIVDEASQISQPICLGPLFFSR
  RFVLVGDHQQLPPLVLNREARALGMSESLFKRLEQNKSAVVQLTVQYRMNSKIMSLSNKL
  TYEGKLECGSDKVANAVINLRHFKDVKLELEFYADYSDNPWLMGVFEPNNPVCFLNTDKV
  PAPEQVEKGGVSNVTEAKLIVFLTSIFVKAGCSPSDIGIIAPYRQQLKIINDLLARSIGM
  VEVNTVDKYQGRDKSIVLVSFVRSNKDGTVGELLKDWRRLNVAITRAKHKLILLGCVPSL
  NCYPPLEKLLNHLNSEKLIIDLPSREHESLCHILGDFQRE
• Function: Key enzyme involved in DNA replication and DNA repair in nucleus and mitochondrion. Involved in Okazaki fragments processing by cleaving long flaps that escape FEN1: flaps that are longer than 27 nucleotides are coated by replication protein A complex (RPA), leading to recruit DNA2 which cleaves the flap until it is too short to bind RPA and becomes a substrate for FEN1. Also involved in 5'-end resection of DNA during double-strand break (DSB) repair: recruited by BLM and mediates the cleavage of 5'-ssDNA, while the 3'-ssDNA cleavage is prevented by the presence of RPA. Also involved in DNA replication checkpoint independently of Okazaki fragments processing. Possesses different enzymatic activities, such as single-stranded DNA (ssDNA)-dependent ATPase, 5'-3' helicase and endonuclease activities. While the ATPase and endonuclease activities are well-defined and play a key role in Okazaki fragments processing and DSB repair, the 5'-3' DNA helicase activity is subject to debate. According to various reports, the helicase activity is weak and its function remains largely unclear. Helicase activity may promote the motion of DNA2 on the flap, helping the nuclease function.
• KEGG Pathway: D. replication (hsa03030)
• Reactome Pathway:
  HDR through Single Strand Annealing (SSA) (R-HSA-5685938)
  HDR through Homologous Recombination (HRR) (R-HSA-5685942)
  Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA) (R-HSA-5693554)
  Resolution of D-loop Structures through Holliday Junction Intermediates (R-HSA-5693568)
  Homologous DNA Pairing and Strand Exchange (R-HSA-5693579)
  Processing of DNA double-strand break ends (R-HSA-5693607)
  Presynaptic phase of homologous DNA pairing and strand exchange (R-HSA-5693616)
  Regulation of TP53 Activity through Phosphorylation (R-HSA-6804756)
  Removal of the Flap Intermediate (R-HSA-69166)
  G2/M DNA damage checkpoint (R-HSA-69473)
  Defective homologous recombination repair (HRR) due to BRCA1 loss of function (R-HSA-9701192)
  Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function (R-HSA-9704331)
  Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function (R-HSA-9704646)
  Impaired BRCA2 binding to RAD51 (R-HSA-9709570)
  Impaired BRCA2 binding to PALB2 (R-HSA-9709603)
  Removal of the Flap Intermediate from the C-strand (R-HSA-174437)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Definitive	Genetic Variation	[1]
Breast carcinoma	DIS2UE88	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[4]
Bloom syndrome	DISKXQ7J	Strong	Genetic Variation	[5]
Fanconi anemia complementation group A	DIS8PZLI	Strong	Biomarker	[6]
Fanconi's anemia	DISGW6Q8	Strong	Biomarker	[6]
leukaemia	DISS7D1V	Strong	Altered Expression	[7]
Leukemia	DISNAKFL	Strong	Altered Expression	[7]
Mitochondrial DNA deletion syndrome with progressive myopathy	DISQJ8QT	Strong	Autosomal dominant	[8]
Mitochondrial myopathy	DIS9SA7V	Strong	Genetic Variation	[9]
Myopathy	DISOWG27	Strong	Genetic Variation	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Ovarian cancer	DISZJHAP	Strong	Genetic Variation	[10]
Ptosis	DISJZNIY	Strong	Genetic Variation	[11]
Seckel syndrome 8	DIS16EES	Strong	Autosomal recessive	[12]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[4]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[4]
Pancreatic cancer	DISJC981	moderate	Biomarker	[13]
Werner syndrome	DISZY45W	moderate	Biomarker	[14]
Li-Fraumeni syndrome	DISR64XA	Disputed	Genetic Variation	[15]
Hepatitis B virus infection	DISLQ2XY	Limited	Biomarker	[16]
Myeloproliferative neoplasm	DIS5KAPA	Limited	Genetic Variation	[17]
Seckel syndrome	DISEVUBA	Limited	Genetic Variation	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	DNA replication ATP-dependent helicase/nuclease DNA2 (DNA2) affects the response to substance of Temozolomide.	[35]
DTI-015	DMXZRW0	Approved	DNA replication ATP-dependent helicase/nuclease DNA2 (DNA2) affects the response to substance of DTI-015.	[35]

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 DNA replication ATP-dependent helicase/nuclease DNA2 (DNA2).	[18]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of DNA replication ATP-dependent helicase/nuclease DNA2 (DNA2).	[19]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DNA replication ATP-dependent helicase/nuclease DNA2 (DNA2).	[20]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of DNA replication ATP-dependent helicase/nuclease DNA2 (DNA2).	[21]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of DNA replication ATP-dependent helicase/nuclease DNA2 (DNA2).	[23]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of DNA replication ATP-dependent helicase/nuclease DNA2 (DNA2).	[23]
Selenium	DM25CGV	Approved	Selenium decreases the expression of DNA replication ATP-dependent helicase/nuclease DNA2 (DNA2).	[24]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of DNA replication ATP-dependent helicase/nuclease DNA2 (DNA2).	[25]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of DNA replication ATP-dependent helicase/nuclease DNA2 (DNA2).	[26]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of DNA replication ATP-dependent helicase/nuclease DNA2 (DNA2).	[27]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of DNA replication ATP-dependent helicase/nuclease DNA2 (DNA2).	[28]
Lucanthone	DMZLBUO	Approved	Lucanthone decreases the expression of DNA replication ATP-dependent helicase/nuclease DNA2 (DNA2).	[29]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of DNA replication ATP-dependent helicase/nuclease DNA2 (DNA2).	[30]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of DNA replication ATP-dependent helicase/nuclease DNA2 (DNA2).	[31]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of DNA replication ATP-dependent helicase/nuclease DNA2 (DNA2).	[34]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of DNA replication ATP-dependent helicase/nuclease DNA2 (DNA2).	[22]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of DNA replication ATP-dependent helicase/nuclease DNA2 (DNA2).	[32]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of DNA replication ATP-dependent helicase/nuclease DNA2 (DNA2).	[33]

References

• [1] BRCA1 and CtIP Are Both Required to Recruit Dna2 at Double-Strand Breaks in Homologous Recombination.PLoS One. 2015 Apr 24;10(4):e0124495. doi: 10.1371/journal.pone.0124495. eCollection 2015.
• [2] Multiple roles of DNA2 nuclease/helicase in DNA metabolism, genome stability and human diseases.Nucleic Acids Res. 2020 Jan 10;48(1):16-35. doi: 10.1093/nar/gkz1101.
• [3] Detection of A oligomers based on magnetic-field-assisted separation of aptamer-functionalized Fe(3)O(4) magnetic nanoparticles and BaYF(5):Yb,Er nanoparticles as upconversion fluorescence labels.Talanta. 2017 Aug 1;170:350-357. doi: 10.1016/j.talanta.2017.04.021. Epub 2017 Apr 14.
• [4] Luteolin induces N-acetylation and DNA adduct of 2-aminofluorene accompanying N-acetyltransferase activity and gene expression in human bladder cancer T24 cell line.Anticancer Res. 2003 Jan-Feb;23(1A):355-62.
• [5] RPA Phosphorylation Inhibits DNA Resection.Mol Cell. 2019 Jul 11;75(1):145-153.e5. doi: 10.1016/j.molcel.2019.05.005. Epub 2019 May 29.
• [6] DNA2 and EXO1 in replication-coupled, homology-directed repair and in the interplay between HDR and the FA/BRCA network.Cell Cycle. 2012 Nov 1;11(21):3983-96. doi: 10.4161/cc.22215. Epub 2012 Sep 17.
• [7] The effect of paclitaxel on gene expression and activity of arylamine N-acetyltransferase and DNA-2-aminofluorene adduct formation in human leukemia HL-60 cells.Food Chem Toxicol. 2002 May;40(5):705-13. doi: 10.1016/s0278-6915(01)00129-6.
• [8] Interplay of Mre11 nuclease with Dna2 plus Sgs1 in Rad51-dependent recombinational repair. PLoS One. 2009;4(1):e4267. doi: 10.1371/journal.pone.0004267. Epub 2009 Jan 23.
• [9] Novel mutations in DNA2 associated with myopathy and mtDNA instability.Ann Clin Transl Neurol. 2019 Sep;6(9):1893-1899. doi: 10.1002/acn3.50888. Epub 2019 Sep 2.
• [10] The DNA2 nuclease/helicase is an estrogen-dependent gene mutated in breast and ovarian cancers.Oncotarget. 2014 Oct 15;5(19):9396-409. doi: 10.18632/oncotarget.2414.
• [11] Novel truncating variant in DNA2-related congenital onset myopathy and ptosis suggests genotype-phenotype correlation.Neuromuscul Disord. 2017 Jul;27(7):616-618. doi: 10.1016/j.nmd.2017.03.013. Epub 2017 Apr 6.
• [12] Genomic analysis of primordial dwarfism reveals novel disease genes. Genome Res. 2014 Feb;24(2):291-9. doi: 10.1101/gr.160572.113. Epub 2014 Jan 3.
• [13] Screening and identification of hub genes in pancreatic cancer by integrated bioinformatics analysis.J Cell Biochem. 2019 Dec;120(12):19496-19508. doi: 10.1002/jcb.29253. Epub 2019 Jul 11.
• [14] The Caenorhabditis elegans WRN helicase promotes double-strand DNA break repair by mediating end resection and checkpoint activation.FEBS Lett. 2017 Jul;591(14):2155-2166. doi: 10.1002/1873-3468.12724. Epub 2017 Jul 4.
• [15] Methylation profile of the promoter CpG islands of 14 "drug-resistance" genes in hepatocellular carcinoma.World J Gastroenterol. 2004 Dec 1;10(23):3433-40. doi: 10.3748/wjg.v10.i23.3433.
• [16] Improvement of Liver Fibrosis after Long-Term Antiviral Therapy Assessed by Fibroscan in Chronic Hepatitis B Patients With Advanced Fibrosis.Am J Gastroenterol. 2017 Jun;112(6):882-891. doi: 10.1038/ajg.2017.93. Epub 2017 Apr 4.
• [17] Biallelic variants in DNA2 cause microcephalic primordial dwarfism.Hum Mutat. 2019 Aug;40(8):1063-1070. doi: 10.1002/humu.23776. Epub 2019 Jun 23.
• [18] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [19] 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.
• [20] 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.
• [21] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [22] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [23] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [24] 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.
• [25] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [26] Cannabidiol-induced transcriptomic changes and cellular senescence in human Sertoli cells. Toxicol Sci. 2023 Feb 17;191(2):227-238. doi: 10.1093/toxsci/kfac131.
• [27] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [28] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [29] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [30] Resveratrol-induced gene expression profiles in human prostate cancer cells. Cancer Epidemiol Biomarkers Prev. 2005 Mar;14(3):596-604. doi: 10.1158/1055-9965.EPI-04-0398.
• [31] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [32] 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.
• [33] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [34] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [35] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.