Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTR2L3Z)

• DOT Name: DNA damage-binding protein 1 (DDB1)
• Synonyms: DDB p127 subunit; DNA damage-binding protein a; DDBa; Damage-specific DNA-binding protein 1; HBV X-associated protein 1; XAP-1; UV-damaged DNA-binding factor; UV-damaged DNA-binding protein 1; UV-DDB 1; XPE-binding factor; XPE-BF; Xeroderma pigmentosum group E-complementing protein; XPCe
• Gene Name: DDB1
• Related Disease:
  Bone osteosarcoma
  Colon cancer
  Gastric cancer
  Gastric neoplasm
  Hepatocellular carcinoma
  Hereditary diffuse gastric adenocarcinoma
  Neoplasm
  Non-small-cell lung cancer
  Osteosarcoma
  Plasma cell myeloma
  Prostate cancer
  Prostate carcinoma
  White-Kernohan syndrome
  Epithelial ovarian cancer
  Head-neck squamous cell carcinoma
  Lung adenocarcinoma
  Ovarian cancer
  Ovarian neoplasm
  Hepatitis B virus infection
  Hepatitis C virus infection
  Melanoma
  Vitelliform macular dystrophy
  Xeroderma pigmentosum
  Xeroderma pigmentosum group E
• UniProt ID: DDB1_HUMAN
• PDB ID: 2B5L ; 2B5M ; 2B5N ; 2HYE ; 3E0C ; 3EI1 ; 3EI2 ; 3EI3 ; 3EI4 ; 3I7H ; 3I7K ; 3I7L ; 3I7N ; 3I7O ; 3I7P ; 3I89 ; 3I8C ; 3I8E ; 4A08 ; 4A09 ; 4A0A ; 4A0B ; 4A0K ; 4A0L ; 4A11 ; 4CI1 ; 4CI2 ; 4CI3 ; 4E54 ; 4E5Z ; 4TZ4 ; 5FQD ; 5HXB ; 5JK7 ; 5V3O ; 6BN7 ; 6BN8 ; 6BN9 ; 6BNB ; 6BOY ; 6DSZ ; 6FCV ; 6H0F ; 6H0G ; 6PAI ; 6Q0R ; 6Q0V ; 6Q0W ; 6R8Y ; 6R8Z ; 6R90 ; 6R91 ; 6R92 ; 6SJ7 ; 6TD3 ; 6UD7 ; 6UE5 ; 6UML ; 6XK9 ; 6ZUE ; 6ZX9 ; 7LPS ; 7OKQ ; 7OO3 ; 7OOB ; 7OOP ; 7OPC ; 7OPD ; 7U8F ; 7UKN ; 7V7B ; 7V7C ; 7ZN7 ; 7ZNN ; 8AJM ; 8AJN ; 8AJO ; 8B3D ; 8B3F ; 8B3I ; 8BU1 ; 8BU2 ; 8BU3 ; 8BU4 ; 8BU5 ; 8BU6 ; 8BU7 ; 8BU9 ; 8BUA ; 8BUB ; 8BUC ; 8BUD ; 8BUE ; 8BUF ; 8BUG ; 8BUH ; 8BUI ; 8BUJ ; 8BUK ; 8BUL ; 8BUM ; 8BUN ; 8BUO ; 8BUP ; 8BUQ ; 8BUR ; 8BUS ; 8BUT ; 8CVP ; 8D7U ; 8D7V ; 8D7W ; 8D7X ; 8D7Y ; 8D7Z ; 8D80 ; 8D81 ; 8DEY ; 8G46 ; 8OIZ ; 8OJH ; 8OV6
• Pfam ID: PF03178 ; PF10433
• Sequence:
  MSYNYVVTAQKPTAVNGCVTGHFTSAEDLNLLIAKNTRLEIYVVTAEGLRPVKEVGMYGK
  IAVMELFRPKGESKDLLFILTAKYNACILEYKQSGESIDIITRAHGNVQDRIGRPSETGI
  IGIIDPECRMIGLRLYDGLFKVIPLDRDNKELKAFNIRLEELHVIDVKFLYGCQAPTICF
  VYQDPQGRHVKTYEVSLREKEFNKGPWKQENVEAEASMVIAVPEPFGGAIIIGQESITYH
  NGDKYLAIAPPIIKQSTIVCHNRVDPNGSRYLLGDMEGRLFMLLLEKEEQMDGTVTLKDL
  RVELLGETSIAECLTYLDNGVVFVGSRLGDSQLVKLNVDSNEQGSYVVAMETFTNLGPIV
  DMCVVDLERQGQGQLVTCSGAFKEGSLRIIRNGIGIHEHASIDLPGIKGLWPLRSDPNRE
  TDDTLVLSFVGQTRVLMLNGEEVEETELMGFVDDQQTFFCGNVAHQQLIQITSASVRLVS
  QEPKALVSEWKEPQAKNISVASCNSSQVVVAVGRALYYLQIHPQELRQISHTEMEHEVAC
  LDITPLGDSNGLSPLCAIGLWTDISARILKLPSFELLHKEMLGGEIIPRSILMTTFESSH
  YLLCALGDGALFYFGLNIETGLLSDRKKVTLGTQPTVLRTFRSLSTTNVFACSDRPTVIY
  SSNHKLVFSNVNLKEVNYMCPLNSDGYPDSLALANNSTLTIGTIDEIQKLHIRTVPLYES
  PRKICYQEVSQCFGVLSSRIEVQDTSGGTTALRPSASTQALSSSVSSSKLFSSSTAPHET
  SFGEEVEVHNLLIIDQHTFEVLHAHQFLQNEYALSLVSCKLGKDPNTYFIVGTAMVYPEE
  AEPKQGRIVVFQYSDGKLQTVAEKEVKGAVYSMVEFNGKLLASINSTVRLYEWTTEKELR
  TECNHYNNIMALYLKTKGDFILVGDLMRSVLLLAYKPMEGNFEEIARDFNPNWMSAVEIL
  DDDNFLGAENAFNLFVCQKDSAATTDEERQHLQEVGLFHLGEFVNVFCHGSLVMQNLGET
  STPTQGSVLFGTVNGMIGLVTSLSESWYNLLLDMQNRLNKVIKSVGKIEHSFWRSFHTER
  KTEPATGFIDGDLIESFLDISRPKMQEVVANLQYDDGSGMKREATADDLIKVVEELTRIH
• Function: Protein, which is both involved in DNA repair and protein ubiquitination, as part of the UV-DDB complex and DCX (DDB1-CUL4-X-box) complexes, respectively. Core component of the UV-DDB complex (UV-damaged DNA-binding protein complex), a complex that recognizes UV-induced DNA damage and recruit proteins of the nucleotide excision repair pathway (the NER pathway) to initiate DNA repair. The UV-DDB complex preferentially binds to cyclobutane pyrimidine dimers (CPD), 6-4 photoproducts (6-4 PP), apurinic sites and short mismatches. Also functions as a component of numerous distinct DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins. The functional specificity of the DCX E3 ubiquitin-protein ligase complex is determined by the variable substrate recognition component recruited by DDB1. DCX(DDB2) (also known as DDB1-CUL4-ROC1, CUL4-DDB-ROC1 and CUL4-DDB-RBX1) may ubiquitinate histone H2A, histone H3 and histone H4 at sites of UV-induced DNA damage. The ubiquitination of histones may facilitate their removal from the nucleosome and promote subsequent DNA repair. DCX(DDB2) also ubiquitinates XPC, which may enhance DNA-binding by XPC and promote NER. DCX(DTL) plays a role in PCNA-dependent polyubiquitination of CDT1 and MDM2-dependent ubiquitination of TP53 in response to radiation-induced DNA damage and during DNA replication. DCX(ERCC8) (the CSA complex) plays a role in transcription-coupled repair (TCR). The DDB1-CUL4A-DTL E3 ligase complex regulates the circadian clock function by mediating the ubiquitination and degradation of CRY1. DDB1-mediated CRY1 degradation promotes FOXO1 protein stability and FOXO1-mediated gluconeogenesis in the liver. By acting on TET dioxygenses, essential for oocyte maintenance at the primordial follicle stage, hence essential for female fertility. Maternal factor required for proper zygotic genome activation and genome reprogramming.
• KEGG Pathway:
  Nucleotide excision repair (hsa03420)
  Ubiquitin mediated proteolysis (hsa04120)
  Hepatitis B (hsa05161)
  Human immunodeficiency virus 1 infection (hsa05170)
  Viral carcinogenesis (hsa05203)
• Reactome Pathway:
  DNA Damage Recognition in GG-NER (R-HSA-5696394)
  Formation of Incision Complex in GG-NER (R-HSA-5696395)
  Dual Incision in GG-NER (R-HSA-5696400)
  Formation of TC-NER Pre-Incision Complex (R-HSA-6781823)
  Transcription-Coupled Nucleotide Excision Repair (TC-NER) (R-HSA-6781827)
  Dual incision in TC-NER (R-HSA-6782135)
  Gap-filling DNA repair synthesis and ligation in TC-NER (R-HSA-6782210)
  Neddylation (R-HSA-8951664)
  Recognition of DNA damage by PCNA-containing replication complex (R-HSA-110314)

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bone osteosarcoma	DIST1004	Strong	Biomarker	[1]
Colon cancer	DISVC52G	Strong	Altered Expression	[2]
Gastric cancer	DISXGOUK	Strong	Biomarker	[3]
Gastric neoplasm	DISOKN4Y	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[4]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[6]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[1]
Plasma cell myeloma	DIS0DFZ0	Strong	Altered Expression	[7]
Prostate cancer	DISF190Y	Strong	Biomarker	[8]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[8]
White-Kernohan syndrome	DISRSWSN	Strong	Autosomal dominant	[9]
Epithelial ovarian cancer	DIS56MH2	moderate	Altered Expression	[10]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Altered Expression	[11]
Lung adenocarcinoma	DISD51WR	moderate	Biomarker	[12]
Ovarian cancer	DISZJHAP	moderate	Altered Expression	[10]
Ovarian neoplasm	DISEAFTY	moderate	Altered Expression	[10]
Hepatitis B virus infection	DISLQ2XY	Limited	Biomarker	[13]
Hepatitis C virus infection	DISQ0M8R	Limited	Biomarker	[14]
Melanoma	DIS1RRCY	Limited	Altered Expression	[15]
Vitelliform macular dystrophy	DISEFYYN	Limited	Biomarker	[16]
Xeroderma pigmentosum	DISQ9H19	Limited	Genetic Variation	[17]
Xeroderma pigmentosum group E	DIS9Q3CA	Limited	Biomarker	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of DNA damage-binding protein 1 (DDB1).	[19]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of DNA damage-binding protein 1 (DDB1).	[20]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of DNA damage-binding protein 1 (DDB1).	[21]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of DNA damage-binding protein 1 (DDB1).	[23]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of DNA damage-binding protein 1 (DDB1).	[24]
Marinol	DM70IK5	Approved	Marinol decreases the expression of DNA damage-binding protein 1 (DDB1).	[25]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of DNA damage-binding protein 1 (DDB1).	[26]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of DNA damage-binding protein 1 (DDB1).	[27]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of DNA damage-binding protein 1 (DDB1).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of DNA damage-binding protein 1 (DDB1).	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the ubiquitination of DNA damage-binding protein 1 (DDB1).	[22]

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Lenalidomide	DM6Q7U4	Approved	Lenalidomide affects the binding of DNA damage-binding protein 1 (DDB1).	[28]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 affects the binding of DNA damage-binding protein 1 (DDB1).	[30]

References

• [1] Small molecule TSC01682 inhibits osteosarcoma cell growth by specifically disrupting the CUL4B-DDB1 interaction and decreasing the ubiquitination of CRL4B E3 ligase substrates.Am J Cancer Res. 2019 Sep 1;9(9):1857-1870. eCollection 2019.
• [2] DDB2 suppresses epithelial-to-mesenchymal transition in colon cancer.Cancer Res. 2013 Jun 15;73(12):3771-82. doi: 10.1158/0008-5472.CAN-12-4069. Epub 2013 Apr 22.
• [3] A gene expression signature of acquired chemoresistance to cisplatin and fluorouracil combination chemotherapy in gastric cancer patients.PLoS One. 2011 Feb 18;6(2):e16694. doi: 10.1371/journal.pone.0016694.
• [4] Hepatitis B virus X protein affects S phase progression leading to chromosome segregation defects by binding to damaged DNA binding protein 1.Hepatology. 2008 Nov;48(5):1467-76. doi: 10.1002/hep.22542.
• [5] Cullin-4ADNA damage-binding protein 1 E3 ligase complex targets tumor suppressor RASSF1A for degradation during mitosis.J Biol Chem. 2011 Mar 4;286(9):6971-8. doi: 10.1074/jbc.M110.186494. Epub 2011 Jan 4.
• [6] CRL4A-FBXW5-mediated degradation of DLC1 Rho GTPase-activating protein tumor suppressor promotes non-small cell lung cancer cell growth.Proc Natl Acad Sci U S A. 2013 Oct 15;110(42):16868-73. doi: 10.1073/pnas.1306358110. Epub 2013 Sep 30.
• [7] Modulation of cereblon levels by anti-myeloma agents.Leuk Lymphoma. 2016;57(1):167-76. doi: 10.3109/10428194.2015.1037752. Epub 2015 May 12.
• [8] NRIP/DCAF6 stabilizes the androgen receptor protein by displacing DDB2 from the CUL4A-DDB1 E3 ligase complex in prostate cancer.Oncotarget. 2017 Mar 28;8(13):21501-21515. doi: 10.18632/oncotarget.15308.
• [9] A DNA repair disorder caused by de novo monoallelic DDB1 variants is associated with a neurodevelopmental syndrome. Am J Hum Genet. 2021 Apr 1;108(4):749-756. doi: 10.1016/j.ajhg.2021.03.007. Epub 2021 Mar 19.
• [10] Cooperation between BRCA1 and p53 in repair of cyclobutane pyrimidine dimers.Cancer Biol Ther. 2005 Dec;4(12):1409-14. doi: 10.4161/cbt.4.12.2378. Epub 2005 Dec 5.
• [11] Reduced mRNA expression of nucleotide excision repair genes in lymphocytes and risk of squamous cell carcinoma of the head and neck.Carcinogenesis. 2017 May 1;38(5):504-510. doi: 10.1093/carcin/bgx028.
• [12] TTF-1/NKX2-1 binds to DDB1 and confers replication stress resistance to lung adenocarcinomas.Oncogene. 2017 Jun 29;36(26):3740-3748. doi: 10.1038/onc.2016.524. Epub 2017 Feb 13.
• [13] A Mass Spectrometry-Based Profiling of Interactomes of Viral DDB1- and Cullin Ubiquitin Ligase-Binding Proteins Reveals NF-B Inhibitory Activity of the HIV-2-Encoded Vpx.Front Immunol. 2018 Dec 19;9:2978. doi: 10.3389/fimmu.2018.02978. eCollection 2018.
• [14] DCAF1 is involved in HCV replication through regulation of miR-122.Arch Virol. 2018 Apr;163(4):977-985. doi: 10.1007/s00705-017-3691-8. Epub 2018 Jan 11.
• [15] Repair of UVB-induced DNA damage is reduced in melanoma due to low XPC and global genome repair.Oncotarget. 2016 Sep 20;7(38):60940-60953. doi: 10.18632/oncotarget.10902.
• [16] Refined mapping of the gene encoding the p127 kDa UV-damaged DNA-binding protein (DDB1) within 11q12-q13.1 and its exclusion in Best's vitelliform macular dystrophy.Eur J Hum Genet. 1998 Jul-Aug;6(4):400-5. doi: 10.1038/sj.ejhg.5200196.
• [17] Dynamics of DDB2-DDB1 complex under different naturally-occurring mutants in Xeroderma Pigmentosum disease.Biochim Biophys Acta Gen Subj. 2018 Dec;1862(12):2579-2589. doi: 10.1016/j.bbagen.2018.08.007. Epub 2018 Aug 6.
• [18] The DDB1-CUL4ADDB2 ubiquitin ligase is deficient in xeroderma pigmentosum group E and targets histone H2A at UV-damaged DNA sites.Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2588-93. doi: 10.1073/pnas.0511160103. Epub 2006 Feb 10.
• [19] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [20] 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.
• [21] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [22] Quantitative Assessment of Arsenite-Induced Perturbation of Ubiquitinated Proteome. Chem Res Toxicol. 2022 Sep 19;35(9):1589-1597. doi: 10.1021/acs.chemrestox.2c00197. Epub 2022 Aug 22.
• [23] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [24] 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.
• [25] Gene expression changes in human small airway epithelial cells exposed to Delta9-tetrahydrocannabinol. Toxicol Lett. 2005 Aug 14;158(2):95-107.
• [26] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [27] Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells. Brain Res. 2006 Oct 20;1116(1):39-49.
• [28] Structure of the human Cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs. Nat Struct Mol Biol. 2014 Sep;21(9):803-9. doi: 10.1038/nsmb.2874. Epub 2014 Aug 10.
• [29] Label-free quantitative proteomic analysis identifies the oncogenic role of FOXA1 in BaP-transformed 16HBE cells. Toxicol Appl Pharmacol. 2020 Sep 15;403:115160. doi: 10.1016/j.taap.2020.115160. Epub 2020 Jul 25.
• [30] "Minimalist" cyclopropene-containing photo-cross-linkers suitable for live-cell imaging and affinity-based protein labeling. J Am Chem Soc. 2014 Jul 16;136(28):9990-8. doi: 10.1021/ja502780z. Epub 2014 Jul 3.
• [31] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.