Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC29RYE)

DOT Name Denticleless protein homolog (DTL)
Synonyms DDB1- and CUL4-associated factor 2; Lethal(2) denticleless protein homolog; Retinoic acid-regulated nuclear matrix-associated protein
Gene Name DTL
UniProt ID
DTL_HUMAN
3D Structure
Download
2D Sequence (FASTA)
Download
3D Structure (PDB)
Download
PDB ID
6QC0
Pfam ID
PF00400
Sequence
MLFNSVLRQPQLGVLRNGWSSQYPLQSLLTGYQCSGNDEHTSYGETGVPVPPFGCTFSSA
PNMEHVLAVANEEGFVRLYNTESQSFRKKCFKEWMAHWNAVFDLAWVPGELKLVTAAGDQ
TAKFWDVKAGELIGTCKGHQCSLKSVAFSKFEKAVFCTGGRDGNIMVWDTRCNKKDGFYR
QVNQISGAHNTSDKQTPSKPKKKQNSKGLAPSVDFQQSVTVVLFQDENTLVSAGAVDGII
KVWDLRKNYTAYRQEPIASKSFLYPGSSTRKLGYSSLILDSTGSTLFANCTDDNIYMFNM
TGLKTSPVAIFNGHQNSTFYVKSSLSPDDQFLVSGSSDEAAYIWKVSTPWQPPTVLLGHS
QEVTSVCWCPSDFTKIATCSDDNTLKIWRLNRGLEEKPGGDKLSTVGWASQKKKESRPGL
VTVTSSQSTPAKAPRAKCNPSNSSPSSAACAPSCAGDLPLPSNTPTFSIKTSPAKARSPI
NRRGSVSSVSPKPPSSFKMSIRNWVTRTPSSSPPITPPASETKIMSPRKALIPVSQKSSQ
AEACSESRNRVKRRLDSSCLESVKQKCVKSCNCVTELDGQVENLHLDLCCLAGNQEDLSK
DSLGPTKSSKIEGAGTSISEPPSPISPYASESCGTLPLPLRPCGEGSEMVGKENSSPENK
NWLLAMAAKRKAENPSPRSPSSQTPNSRRQSGKKLPSPVTITPSSMRKICTYFHRKSQED
FCGPEHSTEL
Function
Substrate-specific adapter of a DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex required for cell cycle control, DNA damage response and translesion DNA synthesis. The DCX(DTL) complex, also named CRL4(CDT2) complex, mediates the polyubiquitination and subsequent degradation of CDT1, CDKN1A/p21(CIP1), FBH1, KMT5A and SDE2. CDT1 degradation in response to DNA damage is necessary to ensure proper cell cycle regulation of DNA replication. CDKN1A/p21(CIP1) degradation during S phase or following UV irradiation is essential to control replication licensing. KMT5A degradation is also important for a proper regulation of mechanisms such as TGF-beta signaling, cell cycle progression, DNA repair and cell migration. Most substrates require their interaction with PCNA for their polyubiquitination: substrates interact with PCNA via their PIP-box, and those containing the 'K+4' motif in the PIP box, recruit the DCX(DTL) complex, leading to their degradation. In undamaged proliferating cells, the DCX(DTL) complex also promotes the 'Lys-164' monoubiquitination of PCNA, thereby being involved in PCNA-dependent translesion DNA synthesis. The DDB1-CUL4A-DTL E3 ligase complex regulates the circadian clock function by mediating the ubiquitination and degradation of CRY1.
Tissue Specificity
Expressed in placenta and testis, very low expression seen in skeletal muscle. Detected in all hematopoietic tissues examined, with highest expression in thymus and bone marrow. A low level detected in the spleen and lymph node, and barely detectable level in the peripheral leukocytes. RA treatment down-regulated the expression in NT2 cell.
Reactome Pathway
Neddylation (R-HSA-8951664 )
Recognition of DNA damage by PCNA-containing replication complex (R-HSA-110314 )

Molecular Interaction Atlas (MIA) of This DOT

Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
6 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate decreases the methylation of Denticleless protein homolog (DTL). [1]
Arsenic trioxide DM61TA4 Approved Arsenic trioxide increases the sumoylation of Denticleless protein homolog (DTL). [9]
TAK-243 DM4GKV2 Phase 1 TAK-243 increases the sumoylation of Denticleless protein homolog (DTL). [25]
PMID28870136-Compound-52 DMFDERP Patented PMID28870136-Compound-52 affects the phosphorylation of Denticleless protein homolog (DTL). [27]
Coumarin DM0N8ZM Investigative Coumarin affects the phosphorylation of Denticleless protein homolog (DTL). [27]
Hexadecanoic acid DMWUXDZ Investigative Hexadecanoic acid increases the phosphorylation of Denticleless protein homolog (DTL). [32]
------------------------------------------------------------------------------------
⏷ Show the Full List of 6 Drug(s)
29 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Ciclosporin DMAZJFX Approved Ciclosporin decreases the expression of Denticleless protein homolog (DTL). [2]
Tretinoin DM49DUI Approved Tretinoin decreases the expression of Denticleless protein homolog (DTL). [3]
Acetaminophen DMUIE76 Approved Acetaminophen decreases the expression of Denticleless protein homolog (DTL). [4]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of Denticleless protein homolog (DTL). [5]
Cisplatin DMRHGI9 Approved Cisplatin increases the expression of Denticleless protein homolog (DTL). [6]
Estradiol DMUNTE3 Approved Estradiol increases the expression of Denticleless protein homolog (DTL). [7]
Quercetin DM3NC4M Approved Quercetin increases the expression of Denticleless protein homolog (DTL). [8]
Calcitriol DM8ZVJ7 Approved Calcitriol decreases the expression of Denticleless protein homolog (DTL). [10]
Testosterone DM7HUNW Approved Testosterone decreases the expression of Denticleless protein homolog (DTL). [10]
Triclosan DMZUR4N Approved Triclosan decreases the expression of Denticleless protein homolog (DTL). [11]
Carbamazepine DMZOLBI Approved Carbamazepine affects the expression of Denticleless protein homolog (DTL). [12]
Progesterone DMUY35B Approved Progesterone decreases the expression of Denticleless protein homolog (DTL). [13]
Demecolcine DMCZQGK Approved Demecolcine decreases the expression of Denticleless protein homolog (DTL). [14]
Niclosamide DMJAGXQ Approved Niclosamide decreases the expression of Denticleless protein homolog (DTL). [15]
Azathioprine DMMZSXQ Approved Azathioprine decreases the expression of Denticleless protein homolog (DTL). [16]
Piroxicam DMTK234 Approved Piroxicam decreases the expression of Denticleless protein homolog (DTL). [17]
Dasatinib DMJV2EK Approved Dasatinib decreases the expression of Denticleless protein homolog (DTL). [18]
Ethinyl estradiol DMODJ40 Approved Ethinyl estradiol increases the expression of Denticleless protein homolog (DTL). [19]
Lucanthone DMZLBUO Approved Lucanthone decreases the expression of Denticleless protein homolog (DTL). [20]
Methamphetamine DMPM4SK Approved Methamphetamine decreases the expression of Denticleless protein homolog (DTL). [21]
Urethane DM7NSI0 Phase 4 Urethane decreases the expression of Denticleless protein homolog (DTL). [22]
Genistein DM0JETC Phase 2/3 Genistein increases the expression of Denticleless protein homolog (DTL). [7]
GSK2110183 DMZHB37 Phase 2 GSK2110183 decreases the expression of Denticleless protein homolog (DTL). [23]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene decreases the expression of Denticleless protein homolog (DTL). [24]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 decreases the expression of Denticleless protein homolog (DTL). [26]
Piperazinyl methyl quinazolinone derivative 2 DM913KS Patented Piperazinyl methyl quinazolinone derivative 2 increases the expression of Denticleless protein homolog (DTL). [28]
THAPSIGARGIN DMDMQIE Preclinical THAPSIGARGIN decreases the expression of Denticleless protein homolog (DTL). [29]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the expression of Denticleless protein homolog (DTL). [30]
Milchsaure DM462BT Investigative Milchsaure increases the expression of Denticleless protein homolog (DTL). [31]
------------------------------------------------------------------------------------
⏷ Show the Full List of 29 Drug(s)

References

1 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.
2 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.
3 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.
4 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.
5 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.
6 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.
7 Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells. Carcinogenesis. 2006 Aug;27(8):1567-78.
8 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.
9 Arsenic-induced sumoylation of Mus81 is involved in regulating genomic stability. Cell Cycle. 2017 Apr 18;16(8):802-811. doi: 10.1080/15384101.2017.1302628. Epub 2017 Mar 20.
10 Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
11 Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
12 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.
13 Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
14 Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
15 Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
16 A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
17 Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
18 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.
19 The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
20 Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
21 Methamphetamine alters the normal progression by inducing cell cycle arrest in astrocytes. PLoS One. 2014 Oct 7;9(10):e109603.
22 Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
23 Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
24 Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
25 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.
26 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.
27 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.
28 A novel circular RNA confers trastuzumab resistance in human epidermal growth factor receptor 2-positive breast cancer through regulating ferroptosis. Environ Toxicol. 2022 Jul;37(7):1597-1607. doi: 10.1002/tox.23509. Epub 2022 Mar 2.
29 Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
30 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.
31 Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
32 Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.