Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT59LSW7)

• DOT Name: ATP-dependent DNA helicase Q4 (RECQL4)
• Synonyms: EC 5.6.2.4; DNA 3'-5' helicase RecQ4; DNA helicase, RecQ-like type 4; RecQ4; RTS; RecQ protein-like 4
• Gene Name: RECQL4
• Related Disease:
  Baller-Gerold syndrome
  Pancytopenia
  Rothmund-Thomson syndrome
  Rothmund-Thomson syndrome type 2
  Adult glioblastoma
  Adult lymphoma
  Bloom syndrome
  Carcinoma
  Cervical cancer
  Cervical carcinoma
  Exanthem
  Gastric cancer
  Glioblastoma multiforme
  Glioma
  Herpes zoster
  Intellectual disability
  Laryngeal disorder
  leukaemia
  Leukemia
  Lung cancer
  Lung carcinoma
  Lymphoma
  Malaria
  Melanoma
  Meningitis
  Neoplasm
  Osteosarcoma
  Pediatric lymphoma
  Plasmodium falciparum malaria
  Prostate cancer
  Prostate carcinoma
  Rabies
  Rapadilino syndrome
  Retinoblastoma
  Rubinstein-Taybi syndrome
  Sleep apnea syndrome
  T-cell lymphoma
  Werner syndrome
  Breast cancer
  Breast carcinoma
  Craniosynostosis
  Fanconi anemia complementation group A
  Fanconi's anemia
  Li-Fraumeni syndrome
  Carcinoma of liver and intrahepatic biliary tract
  Cutaneous mastocytosis
  Hepatocellular carcinoma
  Liver cancer
  Pneumocystis pneumonia
• UniProt ID: RECQ4_HUMAN
• PDB ID: 2KMU; 5LST
• EC Number: 5.6.2.4
• Pfam ID: PF00270 ; PF11719 ; PF00271
• Sequence:
  MERLRDVRERLQAWERAFRRQRGRRPSQDDVEAAPEETRALYREYRTLKRTTGQAGGGLR
  SSESLPAAAEEAPEPRCWGPHLNRAATKSPQSTPGRSRQGSVPDYGQRLKANLKGTLQAG
  PALGRRPWPLGRASSKASTPKPPGTGPVPSFAEKVSDEPPQLPEPQPRPGRLQHLQASLS
  QRLGSLDPGWLQRCHSEVPDFLGAPKACRPDLGSEESQLLIPGESAVLGPGAGSQGPEAS
  AFQEVSIRVGSPQPSSSGGEKRRWNEEPWESPAQVQQESSQAGPPSEGAGAVAVEEDPPG
  EPVQAQPPQPCSSPSNPRYHGLSPSSQARAGKAEGTAPLHIFPRLARHDRGNYVRLNMKQ
  KHYVRGRALRSRLLRKQAWKQKWRKKGECFGGGGATVTTKESCFLNEQFDHWAAQCPRPA
  SEEDTDAVGPEPLVPSPQPVPEVPSLDPTVLPLYSLGPSGQLAETPAEVFQALEQLGHQA
  FRPGQERAVMRILSGISTLLVLPTGAGKSLCYQLPALLYSRRSPCLTLVVSPLLSLMDDQ
  VSGLPPCLKAACIHSGMTRKQRESVLQKIRAAQVHVLMLTPEALVGAGGLPPAAQLPPVA
  FACIDEAHCLSQWSHNFRPCYLRVCKVLRERMGVHCFLGLTATATRRTASDVAQHLAVAE
  EPDLHGPAPVPTNLHLSVSMDRDTDQALLTLLQGKRFQNLDSIIIYCNRREDTERIAALL
  RTCLHAAWVPGSGGRAPKTTAEAYHAGMCSRERRRVQRAFMQGQLRVVVATVAFGMGLDR
  PDVRAVLHLGLPPSFESYVQAVGRAGRDGQPAHCHLFLQPQGEDLRELRRHVHADSTDFL
  AVKRLVQRVFPACTCTCTRPPSEQEGAVGGERPVPKYPPQEAEQLSHQAAPGPRRVCMGH
  ERALPIQLTVQALDMPEEAIETLLCYLELHPHHWLELLATTYTHCRLNCPGGPAQLQALA
  HRCPPLAVCLAQQLPEDPGQGSSSVEFDMVKLVDSMGWELASVRRALCQLQWDHEPRTGV
  RRGTGVLVEFSELAFHLRSPGDLTAEEKDQICDFLYGRVQARERQALARLRRTFQAFHSV
  AFPSCGPCLEQQDEERSTRLKDLLGRYFEEEEGQEPGGMEDAQGPEPGQARLQDWEDQVR
  CDIRQFLSLRPEEKFSSRAVARIFHGIGSPCYPAQVYGQDRRFWRKYLHLSFHALVGLAT
  EELLQVAR
• Function: An ATP-dependent DNA helicase which unwinds dsDNA with a 3'-overhang in a 3'-5' direction. Does not unwind more than 18 bp of dsDNA. May modulate chromosome segregation. The N-terminal domain (residues 1-54) binds DNA Y-shaped DNA better than ss- or dsDNA. The core helicase domain binds ssDNA.
• Tissue Specificity: Ubiquitously expressed, with highest levels in thymus and testis.

Molecular Interaction Atlas (MIA) of This DOT

49 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Baller-Gerold syndrome	DIS245AL	Definitive	Autosomal recessive	[1]
Pancytopenia	DISVKEHV	Definitive	Biomarker	[2]
Rothmund-Thomson syndrome	DISGVBCV	Definitive	Autosomal recessive	[3]
Rothmund-Thomson syndrome type 2	DISK9SP2	Definitive	Autosomal recessive	[4]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[5]
Adult lymphoma	DISK8IZR	Strong	Biomarker	[6]
Bloom syndrome	DISKXQ7J	Strong	Biomarker	[7]
Carcinoma	DISH9F1N	Strong	Biomarker	[8]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[9]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[9]
Exanthem	DISAFOQN	Strong	Genetic Variation	[10]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[11]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[5]
Glioma	DIS5RPEH	Strong	Biomarker	[12]
Herpes zoster	DISNSMNY	Strong	Biomarker	[13]
Intellectual disability	DISMBNXP	Strong	Biomarker	[6]
Laryngeal disorder	DISDKUQO	Strong	Biomarker	[8]
leukaemia	DISS7D1V	Strong	Biomarker	[14]
Leukemia	DISNAKFL	Strong	Biomarker	[14]
Lung cancer	DISCM4YA	Strong	Biomarker	[15]
Lung carcinoma	DISTR26C	Strong	Biomarker	[15]
Lymphoma	DISN6V4S	Strong	Biomarker	[6]
Malaria	DISQ9Y50	Strong	Biomarker	[16]
Melanoma	DIS1RRCY	Strong	Biomarker	[17]
Meningitis	DISQABAA	Strong	Biomarker	[18]
Neoplasm	DISZKGEW	Strong	Altered Expression	[19]
Osteosarcoma	DISLQ7E2	Strong	Autosomal recessive	[20]
Pediatric lymphoma	DIS51BK2	Strong	Biomarker	[6]
Plasmodium falciparum malaria	DIS3Q9KF	Strong	Biomarker	[21]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[22]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[22]
Rabies	DISSC4V5	Strong	Biomarker	[23]
Rapadilino syndrome	DISJX57C	Strong	Autosomal recessive	[20]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[24]
Rubinstein-Taybi syndrome	DISVF1HM	Strong	Genetic Variation	[25]
Sleep apnea syndrome	DISER6KS	Strong	Biomarker	[26]
T-cell lymphoma	DISSXRTQ	Strong	Genetic Variation	[27]
Werner syndrome	DISZY45W	Strong	Biomarker	[7]
Breast cancer	DIS7DPX1	moderate	Genetic Variation	[28]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[28]
Craniosynostosis	DIS6J405	moderate	Altered Expression	[29]
Fanconi anemia complementation group A	DIS8PZLI	moderate	Genetic Variation	[30]
Fanconi's anemia	DISGW6Q8	moderate	Genetic Variation	[30]
Li-Fraumeni syndrome	DISR64XA	Disputed	Genetic Variation	[31]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Altered Expression	[19]
Cutaneous mastocytosis	DISLBZEF	Limited	Biomarker	[18]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[19]
Liver cancer	DISDE4BI	Limited	Altered Expression	[19]
Pneumocystis pneumonia	DISFSOM3	Limited	Genetic Variation	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of ATP-dependent DNA helicase Q4 (RECQL4).	[33]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of ATP-dependent DNA helicase Q4 (RECQL4).	[34]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of ATP-dependent DNA helicase Q4 (RECQL4).	[35]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of ATP-dependent DNA helicase Q4 (RECQL4).	[36]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of ATP-dependent DNA helicase Q4 (RECQL4).	[37]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of ATP-dependent DNA helicase Q4 (RECQL4).	[38]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of ATP-dependent DNA helicase Q4 (RECQL4).	[38]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of ATP-dependent DNA helicase Q4 (RECQL4).	[39]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of ATP-dependent DNA helicase Q4 (RECQL4).	[40]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of ATP-dependent DNA helicase Q4 (RECQL4).	[41]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of ATP-dependent DNA helicase Q4 (RECQL4).	[42]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of ATP-dependent DNA helicase Q4 (RECQL4).	[43]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of ATP-dependent DNA helicase Q4 (RECQL4).	[44]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of ATP-dependent DNA helicase Q4 (RECQL4).	[45]

References

• [1] Cloning of two new human helicase genes of the RecQ family: biological significance of multiple species in higher eukaryotes. Genomics. 1998 Dec 15;54(3):443-52. doi: 10.1006/geno.1998.5595.
• [2] ATP-dependent helicase activity is dispensable for the physiological functions of Recql4.PLoS Genet. 2019 Jul 5;15(7):e1008266. doi: 10.1371/journal.pgen.1008266. eCollection 2019 Jul.
• [3] 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.
• [4] Rothmund-Thomson syndrome due to RECQ4 helicase mutations: report and clinical and molecular comparisons with Bloom syndrome and Werner syndrome. Am J Med Genet. 2000 Jan 31;90(3):223-8. doi: 10.1002/(sici)1096-8628(20000131)90:3<223::aid-ajmg7>3.0.co;2-z.
• [5] DNA-repair gene variants are associated with glioblastoma survival.Acta Oncol. 2012 Mar;51(3):325-32. doi: 10.3109/0284186X.2011.616284. Epub 2011 Oct 21.
• [6] Rothmund-Thomson syndrome and osteoma cutis in a patient previously diagnosed as COPS syndrome.Eur J Pediatr. 2017 Feb;176(2):279-283. doi: 10.1007/s00431-016-2834-3. Epub 2016 Dec 30.
• [7] Bloom's syndrome: Why not premature aging?: A comparison of the BLM and WRN helicases.Ageing Res Rev. 2017 Jan;33:36-51. doi: 10.1016/j.arr.2016.05.010. Epub 2016 May 26.
• [8] Deletions of N33, STK11 and TP53 are involved in the development of lymph node metastasis in larynx and pharynx carcinomas.Cell Oncol. 2007;29(4):327-34. doi: 10.1155/2007/635962.
• [9] Over expression of minichromosome maintenance genes is clinically correlated to cervical carcinogenesis.PLoS One. 2013 Jul 17;8(7):e69607. doi: 10.1371/journal.pone.0069607. Print 2013.
• [10] Defective sister-chromatid cohesion, aneuploidy and cancer predisposition in a mouse model of type II Rothmund-Thomson syndrome.Hum Mol Genet. 2005 Mar 15;14(6):813-25. doi: 10.1093/hmg/ddi075. Epub 2005 Feb 9.
• [11] Overexpression of RECQL4 is associated with poor prognosis in patients with gastric cancer.Oncol Lett. 2018 Oct;16(4):5419-5425. doi: 10.3892/ol.2018.9318. Epub 2018 Aug 17.
• [12] Regulated intratumoral expression of IL-12 using a RheoSwitch Therapeutic System() (RTS()) gene switch as gene therapy for the treatment of glioma.Cancer Gene Ther. 2018 Jun;25(5-6):106-116. doi: 10.1038/s41417-018-0019-0. Epub 2018 May 14.
• [13] Updated insights into the mechanism of action and clinical profile of the immunoadjuvant QS-21: A review.Phytomedicine. 2019 Jul;60:152905. doi: 10.1016/j.phymed.2019.152905. Epub 2019 Mar 30.
• [14] Realgar transforming solution as a novel arsenic agent with a lower risk of cardiotoxicity.J Pharmacol Sci. 2019 Jun;140(2):162-170. doi: 10.1016/j.jphs.2019.06.003. Epub 2019 Jun 15.
• [15] Variants in DNA double-strand break repair and DNA damage-response genes and susceptibility to lung and head and neck cancers.Int J Cancer. 2008 Jul 15;123(2):457-463. doi: 10.1002/ijc.23524.
• [16] Combining antimalarial drugs and vaccine for malaria elimination campaigns: a randomized safety and immunogenicity trial of RTS,S/AS01 administered with dihydroartemisinin, piperaquine, and primaquine in healthy Thai adult volunteers.Hum Vaccin Immunother. 2020;16(1):33-41. doi: 10.1080/21645515.2019.1643675. Epub 2019 Aug 15.
• [17] On the interplay of telomeres, nevi and the risk of melanoma.PLoS One. 2012;7(12):e52466. doi: 10.1371/journal.pone.0052466. Epub 2012 Dec 27.
• [18] Safety profile of the RTS,S/AS01 malaria vaccine in infants and children: additional data from a phase III randomized controlled trial in sub-Saharan Africa.Hum Vaccin Immunother. 2019;15(10):2386-2398. doi: 10.1080/21645515.2019.1586040. Epub 2019 Apr 23.
• [19] Upregulation of RECQL4 expression predicts poor prognosis in hepatocellular carcinoma.Oncol Lett. 2018 Apr;15(4):4248-4254. doi: 10.3892/ol.2018.7860. Epub 2018 Jan 25.
• [20] Association between osteosarcoma and deleterious mutations in the RECQL4 gene in Rothmund-Thomson syndrome. J Natl Cancer Inst. 2003 May 7;95(9):669-74. doi: 10.1093/jnci/95.9.669.
• [21] Immune response to the hepatitis B antigen in the RTS,S/AS01 malaria vaccine, and co-administration with pneumococcal conjugate and rotavirus vaccines in African children: A randomized controlled trial.Hum Vaccin Immunother. 2018 Jun 3;14(6):1489-1500. doi: 10.1080/21645515.2018.1442996. Epub 2018 Apr 13.
• [22] Targeted next generation sequencing identifies functionally deleterious germline mutations in novel genes in early-onset/familial prostate cancer.PLoS Genet. 2018 Apr 16;14(4):e1007355. doi: 10.1371/journal.pgen.1007355. eCollection 2018 Apr.
• [23] Safety and immunogenicity of the RTS,S/AS01 malaria vaccine in infants and children identified as HIV-infected during a randomized trial in sub-Saharan Africa.Vaccine. 2020 Jan 22;38(4):897-906. doi: 10.1016/j.vaccine.2019.10.077. Epub 2019 Nov 7.
• [24] Array comparative genomic hybridization in osteosarcoma.Methods Mol Biol. 2013;973:227-47. doi: 10.1007/978-1-62703-281-0_15.
• [25] Mosaic CREBBP mutation causes overlapping clinical features of Rubinstein-Taybi and Filippi syndromes.Eur J Hum Genet. 2016 Aug;24(9):1363-6. doi: 10.1038/ejhg.2016.14. Epub 2016 Mar 9.
• [26] Retinal vein occlusion and obstructive sleep apnea: a series of 114 patients.Acta Ophthalmol. 2018 Dec;96(8):e919-e925. doi: 10.1111/aos.13798. Epub 2018 Sep 6.
• [27] A patient with Baller-Gerold syndrome and midline NK/T lymphoma.Am J Med Genet A. 2009 Feb 15;149A(4):755-9. doi: 10.1002/ajmg.a.32736.
• [28] RECQL4 helicase has oncogenic potential in sporadic breast cancers.J Pathol. 2016 Mar;238(4):495-501. doi: 10.1002/path.4681. Epub 2016 Feb 2.
• [29] RECQL4 Regulates p53 Function In Vivo During Skeletogenesis.J Bone Miner Res. 2015 Jun;30(6):1077-89. doi: 10.1002/jbmr.2436.
• [30] Subependymal giant cell astrocytoma-like astrocytoma: a neoplasm with a distinct phenotype and frequent neurofibromatosis type-1-association.Mod Pathol. 2018 Dec;31(12):1787-1800. doi: 10.1038/s41379-018-0103-x. Epub 2018 Jul 4.
• [31] RECQL4 and p53 potentiate the activity of polymerase and maintain the integrity of the human mitochondrial genome.Carcinogenesis. 2014 Jan;35(1):34-45. doi: 10.1093/carcin/bgt315. Epub 2013 Sep 25.
• [32] Successful umbilical cord blood stem cell transplantation in a patient with Rothmund-Thomson syndrome and combined immunodeficiency.Clin Genet. 2006 Apr;69(4):337-43. doi: 10.1111/j.1399-0004.2006.00592.x.
• [33] 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.
• [34] 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.
• [35] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [36] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [37] 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.
• [38] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [39] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [40] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [41] Survival of retinal pigment epithelium after exposure to prolonged oxidative injury: a detailed gene expression and cellular analysis. Invest Ophthalmol Vis Sci. 2004 Oct;45(10):3767-77.
• [42] 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.
• [43] 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.
• [44] 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.
• [45] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.