Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1WR3MD)

• DOT Name: ATP-dependent DNA helicase DDX11 (DDX11)
• Synonyms: EC 3.6.4.12; CHL1-related protein 1; hCHLR1; DEAD/H-box protein 11; Keratinocyte growth factor-regulated gene 2 protein; KRG-2
• Gene Name: DDX11
• Related Disease:
  Melanoma
  Warsaw breakage syndrome
  Beckwith-Wiedemann syndrome
  Colorectal carcinoma
  Cornelia de Lange syndrome
  Dyskeratosis congenita
  Fanconi anemia complementation group A
  Fanconi's anemia
  Roberts-SC phocomelia syndrome
  Xeroderma pigmentosum
  Advanced cancer
  Isolated congenital microcephaly
  Metastatic melanoma
  Neoplasm
• UniProt ID: DDX11_HUMAN
• EC Number: 3.6.4.12
• Pfam ID: PF06733 ; PF13307
• Sequence:
  MANETQKVGAIHFPFPFTPYSIQEDFMAELYRVLEAGKIGIFESPTGTGKSLSLICGALS
  WLRDFEQKKREEEARLLETGTGPLHDEKDESLCLSSSCEGAAGTPRPAGEPAWVTQFVQK
  KEERDLVDRLKAEQARRKQREERLQQLQHRVQLKYAAKRLRQEEEERENLLRLSREMLET
  GPEAERLEQLESGEEELVLAEYESDEEKKVASRVDEDEDDLEEEHITKIYYCSRTHSQLA
  QFVHEVKKSPFGKDVRLVSLGSRQNLCVNEDVKSLGSVQLINDRCVDMQRSRHEKKKGAE
  EEKPKRRRQEKQAACPFYNHEQMGLLRDEALAEVKDMEQLLALGKEARACPYYGSRLAIP
  AAQLVVLPYQMLLHAATRQAAGIRLQDQVVIIDEAHNLIDTITGMHSVEVSGSQLCQAHS
  QLLQYVERYGKRLKAKNLMYLKQILYLLEKFVAVLGGNIKQNPNTQSLSQTGTELKTIND
  FLFQSQIDNINLFKVQRYCEKSMISRKLFGFTERYGAVFSSREQPKLAGFQQFLQSLQPR
  TTEALAAPADESQASTLRPASPLMHIQGFLAALTTANQDGRVILSRQGSLSQSTLKFLLL
  NPAVHFAQVVKECRAVVIAGGTMQPVSDFRQQLLACAGVEAERVVEFSCGHVIPPDNILP
  LVICSGISNQPLEFTFQKRELPQMMDEVGRILCNLCGVVPGGVVCFFPSYEYLRQVHAHW
  EKGGLLGRLAARKKIFQEPKSAHQVEQVLLAYSRCIQACGQERGQVTGALLLSVVGGKMS
  EGINFSDNLGRCVVMVGMPFPNIRSAELQEKMAYLDQTLSPRPGTPREGSGGEPVHEGRQ
  PVHRQGHQAPEGFCQRSAPGPAICPAPCPGQAAGLDPSPCGGQSYLWPRHCCCAEVSPGE
  VGLFLMGNHTTAWRRALPLSCPLETVFVVGVVCGDPVTKVKPRRRVWSPECCQDPGTGVS
  SRRRKWGNPE
• Function: DNA-dependent ATPase and ATP-dependent DNA helicase that participates in various functions in genomic stability, including DNA replication, DNA repair and heterochromatin organization as well as in ribosomal RNA synthesis. Its double-stranded DNA helicase activity requires either a minimal 5'-single-stranded tail length of approximately 15 nt (flap substrates) or 10 nt length single-stranded gapped DNA substrates of a partial duplex DNA structure for helicase loading and translocation along DNA in a 5' to 3' direction. The helicase activity is capable of displacing duplex regions up to 100 bp, which can be extended up to 500 bp by the replication protein A (RPA) or the cohesion CTF18-replication factor C (Ctf18-RFC) complex activities. Shows also ATPase- and helicase activities on substrates that mimic key DNA intermediates of replication, repair and homologous recombination reactions, including forked duplex, anti-parallel G-quadruplex and three-stranded D-loop DNA molecules. Plays a role in DNA double-strand break (DSB) repair at the DNA replication fork during DNA replication recovery from DNA damage. Recruited with TIMELESS factor upon DNA-replication stress response at DNA replication fork to preserve replication fork progression, and hence ensure DNA replication fidelity. Cooperates also with TIMELESS factor during DNA replication to regulate proper sister chromatid cohesion and mitotic chromosome segregation. Stimulates 5'-single-stranded DNA flap endonuclease activity of FEN1 in an ATP- and helicase-independent manner; and hence it may contribute in Okazaki fragment processing at DNA replication fork during lagging strand DNA synthesis. Its ability to function at DNA replication fork is modulated by its binding to long non-coding RNA (lncRNA) cohesion regulator non-coding RNA DDX11-AS1/CONCR, which is able to increase both DDX11 ATPase activity and binding to DNA replicating regions. Also plays a role in heterochromatin organization. Involved in rRNA transcription activation through binding to active hypomethylated rDNA gene loci by recruiting UBTF and the RNA polymerase Pol I transcriptional machinery. Plays a role in embryonic development and prevention of aneuploidy. Involved in melanoma cell proliferation and survival. Associates with chromatin at DNA replication fork regions. Binds to single- and double-stranded DNAs ; (Microbial infection) Required for bovine papillomavirus type 1 regulatory protein E2 loading onto mitotic chromosomes during DNA replication for the viral genome to be maintained and segregated.
• Tissue Specificity: Expressed in melanoma cells. Not detected in epidermal melanocytes of normal skin (at protein level) . Highly expressed in spleen, B-cells, thymus, testis, ovary, small intestine and pancreas . Very low expression seen in brain . Expressed in dividing cells and/or cells undergoing high levels of recombination . No expression detected in cells signaled to terminally differentiate . Expressed weakly in keratinocytes .
• KEGG Pathway: Cell cycle (hsa04110)
• Reactome Pathway: XBP1(S) activates chaperone genes (R-HSA-381038)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Melanoma	DIS1RRCY	Definitive	Biomarker	[1]
Warsaw breakage syndrome	DIS1AE2E	Definitive	Autosomal recessive	[2]
Beckwith-Wiedemann syndrome	DISH15GR	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Cornelia de Lange syndrome	DISEQSXO	Strong	Biomarker	[5]
Dyskeratosis congenita	DISSXV0K	Strong	Genetic Variation	[6]
Fanconi anemia complementation group A	DIS8PZLI	Strong	Biomarker	[7]
Fanconi's anemia	DISGW6Q8	Strong	Biomarker	[7]
Roberts-SC phocomelia syndrome	DIS4JXZ4	Strong	Biomarker	[5]
Xeroderma pigmentosum	DISQ9H19	Strong	Genetic Variation	[6]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[8]
Isolated congenital microcephaly	DISUXHZ6	moderate	Genetic Variation	[2]
Metastatic melanoma	DISSL43L	Limited	Altered Expression	[9]
Neoplasm	DISZKGEW	Limited	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of ATP-dependent DNA helicase DDX11 (DDX11).	[11]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of ATP-dependent DNA helicase DDX11 (DDX11).	[13]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of ATP-dependent DNA helicase DDX11 (DDX11).	[14]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of ATP-dependent DNA helicase DDX11 (DDX11).	[14]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of ATP-dependent DNA helicase DDX11 (DDX11).	[15]
Malathion	DMXZ84M	Approved	Malathion increases the expression of ATP-dependent DNA helicase DDX11 (DDX11).	[16]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of ATP-dependent DNA helicase DDX11 (DDX11).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of ATP-dependent DNA helicase DDX11 (DDX11).	[18]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of ATP-dependent DNA helicase DDX11 (DDX11).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of ATP-dependent DNA helicase DDX11 (DDX11).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of ATP-dependent DNA helicase DDX11 (DDX11).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of ATP-dependent DNA helicase DDX11 (DDX11).	[23]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of ATP-dependent DNA helicase DDX11 (DDX11).	[24]

2 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 ATP-dependent DNA helicase DDX11 (DDX11).	[12]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of ATP-dependent DNA helicase DDX11 (DDX11).	[20]

References

• [1] Targeting negative regulation of p53 by MDM2 and WIP1 as a therapeutic strategy in cutaneous melanoma.Br J Cancer. 2018 Feb 20;118(4):495-508. doi: 10.1038/bjc.2017.433. Epub 2017 Dec 12.
• [2] Identification and biochemical characterization of a novel mutation in DDX11 causing Warsaw breakage syndrome. Hum Mutat. 2013 Jan;34(1):103-7. doi: 10.1002/humu.22226. Epub 2012 Oct 17.
• [3] Warsaw breakage syndrome: Further clinical and genetic delineation.Am J Med Genet A. 2018 Nov;176(11):2404-2418. doi: 10.1002/ajmg.a.40482. Epub 2018 Sep 14.
• [4] Long noncoding RNA DDX11-AS1 induced by YY1 accelerates colorectal cancer progression through targeting miR-873/CLDN7 axis.Eur Rev Med Pharmacol Sci. 2019 Jul;23(13):5714-5729. doi: 10.26355/eurrev_201907_18309.
• [5] Warsaw breakage syndrome, a cohesinopathy associated with mutations in the XPD helicase family member DDX11/ChlR1.Am J Hum Genet. 2010 Feb 12;86(2):262-6. doi: 10.1016/j.ajhg.2010.01.008. Epub 2010 Feb 4.
• [6] Specialization among iron-sulfur cluster helicases to resolve G-quadruplex DNA structures that threaten genomic stability.J Biol Chem. 2013 Sep 27;288(39):28217-29. doi: 10.1074/jbc.M113.496463. Epub 2013 Aug 9.
• [7] Warsaw breakage syndrome DDX11 helicase acts jointly with RAD17 in the repair of bulky lesions and replication through abasic sites.Proc Natl Acad Sci U S A. 2018 Aug 14;115(33):8412-8417. doi: 10.1073/pnas.1803110115. Epub 2018 Jul 30.
• [8] Molecular functions and cellular roles of the ChlR1 (DDX11) helicase defective in the rare cohesinopathy Warsaw breakage syndrome.Cell Mol Life Sci. 2014 Jul;71(14):2625-39. doi: 10.1007/s00018-014-1569-4. Epub 2014 Feb 1.
• [9] The DEAD/DEAH box helicase, DDX11, is essential for the survival of advanced melanomas.Mol Cancer. 2012 Nov 1;11:82. doi: 10.1186/1476-4598-11-82.
• [10] Non invasive imaging assessment of the biodistribution of GSK2849330, an ADCC and CDC optimized anti HER3 mAb, and its role in tumor macrophage recruitment in human tumor-bearing mice.PLoS One. 2017 Apr 27;12(4):e0176075. doi: 10.1371/journal.pone.0176075. eCollection 2017.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [15] 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.
• [16] Malathion induced cancer-linked gene expression in human lymphocytes. Environ Res. 2020 Mar;182:109131. doi: 10.1016/j.envres.2020.109131. Epub 2020 Jan 10.
• [17] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [18] 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.
• [19] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] MCM-2 is a therapeutic target of Trichostatin A in colon cancer cells. Toxicol Lett. 2013 Jul 31;221(1):23-30. doi: 10.1016/j.toxlet.2013.05.643. Epub 2013 Jun 13.
• [24] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.