Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVZMP1Q)

• DOT Name: ATP-dependent DNA helicase Q5 (RECQL5)
• Synonyms: EC 5.6.2.4; DNA 3'-5' helicase RecQ5; DNA helicase, RecQ-like type 5; RecQ5; RecQ protein-like 5
• Gene Name: RECQL5
• Related Disease:
  Bladder cancer
  Bone osteosarcoma
  Colon cancer
  Colon carcinoma
  Head and neck cancer
  Head and neck carcinoma
  Laryngeal carcinoma
  Myocardial infarction
  Neoplasm
  Osteosarcoma
  Triple negative breast cancer
  Breast carcinoma
  Familial partial lipodystrophy
  Hereditary breast carcinoma
  Breast cancer
  Coronary heart disease
  Myeloproliferative neoplasm
  Werner syndrome
• UniProt ID: RECQ5_HUMAN
• PDB ID: 4BK0; 5LB3; 5LB5; 5LB8; 5LBA; 7ZML; 7ZMM; 7ZMN; 7ZMO; 7ZMP; 7ZMQ; 7ZMR; 7ZMS; 7ZMT; 7ZMV
• EC Number: 5.6.2.4
• Pfam ID: PF00270 ; PF00271 ; PF06959 ; PF16124
• Sequence:
  MSSHHTTFPFDPERRVRSTLKKVFGFDSFKTPLQESATMAVVKGNKDVFVCMPTGAGKSL
  CYQLPALLAKGITIVVSPLIALIQDQVDHLLTLKVRVSSLNSKLSAQERKELLADLEREK
  PQTKILYITPEMAASSSFQPTLNSLVSRHLLSYLVVDEAHCVSQWGHDFRPDYLRLGALR
  SRLGHAPCVALTATATPQVQEDVFAALHLKKPVAIFKTPCFRANLFYDVQFKELISDPYG
  NLKDFCLKALGQEADKGLSGCGIVYCRTREACEQLAIELSCRGVNAKAYHAGLKASERTL
  VQNDWMEEKVPVIVATISFGMGVDKANVRFVAHWNIAKSMAGYYQESGRAGRDGKPSWCR
  LYYSRNDRDQVSFLIRKEVAKLQEKRGNKASDKATIMAFDALVTFCEELGCRHAAIAKYF
  GDALPACAKGCDHCQNPTAVRRRLEALERSSSWSKTCIGPSQGNGFDPELYEGGRKGYGD
  FSRYDEGSGGSGDEGRDEAHKREWNLFYQKQMQLRKGKDPKIEEFVPPDENCPLKEASSR
  RIPRLTVKAREHCLRLLEEALSSNRQSTRTADEADLRAKAVELEHETFRNAKVANLYKAS
  VLKKVADIHRASKDGQPYDMGGSAKSCSAQAEPPEPNEYDIPPASHVYSLKPKRVGAGFP
  KGSCPFQTATELMETTRIREQAPQPERGGEHEPPSRPCGLLDEDGSEPLPGPRGEVPGGS
  AHYGGPSPEKKAKSSSGGSSLAKGRASKKQQLLATAAHKDSQSIARFFCRRVESPALLAS
  APEAEGACPSCEGVQGPPMAPEKYTGEEDGAGGHSPAPPQTEECLRERPSTCPPRDQGTP
  EVQPTPAKDTWKGKRPRSQQENPESQPQKRPRPSAKPSVVAEVKGSVSASEQGTLNPTAQ
  DPFQLSAPGVSLKEAANVVVKCLTPFYKEGKFASKELFKGFARHLSHLLTQKTSPGRSVK
  EEAQNLIRHFFHGRARCESEADWHGLCGPQR
• Function: DNA helicase that plays an important role in DNA replication, transcription and repair. Probably unwinds DNA in a 3'-5' direction (Probable). Binds to the RNA polymerase II subunit POLR2A during transcription elongation and suppresses transcription-associated genomic instability. Associates also with POLR1A and enforces the stability of ribosomal DNA arrays. Plays an important role in mitotic chromosome separation after cross-over events and cell cycle progress. Mechanistically, removes RAD51 filaments protecting stalled replication forks at common fragile sites and stimulates MUS81-EME1 endonuclease leading to mitotic DNA synthesis. Required for efficient DNA repair, including repair of inter-strand cross-links. Stimulates DNA decatenation mediated by TOP2A. Prevents sister chromatid exchange and homologous recombination. A core helicase fragment (residues 11-609) binds preferentially to splayed duplex, looped and ssDNA.
• Tissue Specificity: Ubiquitous.

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bladder cancer	DISUHNM0	Strong	Altered Expression	[1]
Bone osteosarcoma	DIST1004	Strong	Genetic Variation	[2]
Colon cancer	DISVC52G	Strong	Biomarker	[3]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[3]
Head and neck cancer	DISBPSQZ	Strong	Genetic Variation	[4]
Head and neck carcinoma	DISOU1DS	Strong	Genetic Variation	[4]
Laryngeal carcinoma	DISNHCIV	Strong	Genetic Variation	[5]
Myocardial infarction	DIS655KI	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Osteosarcoma	DISLQ7E2	Strong	Genetic Variation	[2]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[8]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[9]
Familial partial lipodystrophy	DISFVL9J	moderate	Biomarker	[10]
Hereditary breast carcinoma	DISAEZT5	moderate	Biomarker	[11]
Breast cancer	DIS7DPX1	Limited	Autosomal dominant	[12]
Coronary heart disease	DIS5OIP1	Limited	Autosomal recessive	[12]
Myeloproliferative neoplasm	DIS5KAPA	Limited	Biomarker	[13]
Werner syndrome	DISZY45W	Limited	Biomarker	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of ATP-dependent DNA helicase Q5 (RECQL5).	[15]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of ATP-dependent DNA helicase Q5 (RECQL5).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of ATP-dependent DNA helicase Q5 (RECQL5).	[17]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of ATP-dependent DNA helicase Q5 (RECQL5).	[18]
Selenium	DM25CGV	Approved	Selenium increases the expression of ATP-dependent DNA helicase Q5 (RECQL5).	[19]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of ATP-dependent DNA helicase Q5 (RECQL5).	[18]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol decreases the expression of ATP-dependent DNA helicase Q5 (RECQL5).	[20]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of ATP-dependent DNA helicase Q5 (RECQL5).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of ATP-dependent DNA helicase Q5 (RECQL5).	[23]

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 ATP-dependent DNA helicase Q5 (RECQL5).	[21]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of ATP-dependent DNA helicase Q5 (RECQL5).	[24]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of ATP-dependent DNA helicase Q5 (RECQL5).	[24]

References

• [1] Altered RECQL5 expression in urothelial bladder carcinoma increases cellular proliferation and makes RECQL5 helicase activity a novel target for chemotherapy.Oncotarget. 2016 Nov 15;7(46):76140-76150. doi: 10.18632/oncotarget.12683.
• [2] Single nucleotide polymorphism in the RECQL5 gene increased osteosarcoma susceptibility in a Chinese Han population.Genet Mol Res. 2015 Mar 13;14(1):1899-902. doi: 10.4238/2015.March.13.18.
• [3] RECQL5 is an important determinant for camptothecin tolerance in human colorectal cancer cells.Biosci Rep. 2011 Oct;31(5):363-9. doi: 10.1042/BSR20100108.
• [4] Assessment of DNA repair susceptibility genes identified by whole exome sequencing in head and neck cancer.DNA Repair (Amst). 2018 Jun-Jul;66-67:50-63. doi: 10.1016/j.dnarep.2018.04.005. Epub 2018 Apr 26.
• [5] Haplotype analysis of RECQL5 gene and laryngeal cancer.Tumour Biol. 2014 Mar;35(3):2669-73. doi: 10.1007/s13277-013-1351-5. Epub 2013 Nov 9.
• [6] Exome Sequencing in a Family Identifies RECQL5 Mutation Resulting in Early Myocardial Infarction.Medicine (Baltimore). 2016 Feb;95(5):e2737. doi: 10.1097/MD.0000000000002737.
• [7] Decreased RECQL5 correlated with disease progression of osteosarcoma.Biochem Biophys Res Commun. 2015 Nov 27;467(4):617-22. doi: 10.1016/j.bbrc.2015.10.114. Epub 2015 Oct 22.
• [8] RECQL5 plays an essential role in maintaining genome stability and viability of triple-negative breast cancer cells.Cancer Med. 2019 Aug;8(10):4743-4752. doi: 10.1002/cam4.2349. Epub 2019 Jun 23.
• [9] Clinicopathological and prognostic significance of RECQL5 helicase expression in breast cancers.Carcinogenesis. 2016 Jan;37(1):63-71. doi: 10.1093/carcin/bgv163. Epub 2015 Nov 19.
• [10] Exploring the pathophysiology behind the more common genetic and acquired lipodystrophies.J Hum Genet. 2014 Jan;59(1):16-23. doi: 10.1038/jhg.2013.107. Epub 2013 Oct 24.
• [11] RECQL5: Another DNA helicase potentially involved in hereditary breast cancer susceptibility.Hum Mutat. 2019 May;40(5):566-577. doi: 10.1002/humu.23732. Epub 2019 Mar 13.
• [12] 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.
• [13] RECQL5 Suppresses Oncogenic JAK2-Induced Replication Stress and Genomic Instability.Cell Rep. 2015 Dec 22;13(11):2345-2352. doi: 10.1016/j.celrep.2015.11.037. Epub 2015 Dec 10.
• [14] RECQL5 plays co-operative and complementary roles with WRN syndrome helicase.Nucleic Acids Res. 2017 Feb 17;45(3):1566. doi: 10.1093/nar/gkw1216.
• [15] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [16] Cyclosporine A--induced oxidative stress in human renal mesangial cells: a role for ERK 1/2 MAPK signaling. Toxicol Sci. 2012 Mar;126(1):101-13.
• [17] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [18] 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.
• [19] 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.
• [20] The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
• [21] 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.
• [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.