Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBVPO66)

• DOT Name: Cilium assembly protein DZIP1 (DZIP1)
• Synonyms: DAZ-interacting protein 1/2; DAZ-interacting zinc finger protein 1
• Gene Name: DZIP1
• Related Disease:
  Breast cancer
  Breast carcinoma
  Spermatogenic failure 47
• UniProt ID: DZIP1_HUMAN
• Pfam ID: PF13815
• Sequence:
  MQAEAADWFSSMPFQKHVYYPLASGPEGPDVAVAAAAAGAASMACAPPSAASGPLPFFQF
  RPRLESVDWRRLSAIDVDKVAGAVDVLTLQENIMNITFCKLEDEKCPHCQSGVDPVLLKL
  IRLAQFTIEYLLHSQEFLTSQLHTLEERLRLSHCDGEQSKKLLTKQAGEIKTLKEECKRR
  KKMISTQQLMIEAKANYYQCHFCDKAFMNQAFLQSHIQRRHTEENSHFEYQKNAQIEKLR
  SEIVVLKEELQLTRSELEAAHHASAVRFSKEYEMQKTKEEDFLKLFDRWKEEEKEKLVDE
  MEKVKEMFMKEFKELTSKNSALEYQLSEIQKSNMQIKSNIGTLKDAHEFKEDRSPYPQDF
  HNVMQLLDSQESKWTARVQAIHQEHKKEKGRLLSHIEKLRTSMIDDLNASNVFYKKRIEE
  LGQRLQEQNELIITQRQQIKDFTCNPLNSISEPKGNPLAWQAFESQPAAPAVPMNAPALH
  TLETKSSLPMVHEQAFSSHILEPIEELSEEEKGRENEQKLNNNKMHLRKALKSNSSLTKG
  LRTMVEQNLMEKLETLGINADIRGISSDQLHRVLKSVESERHKQEREIPNFHQIREFLEH
  QVSCKIEEKALLSSDQCSVSQMDTLSTGEVPKMIQLPSKNRQLIRQKAVSTDRTSVPKIK
  KNVMEDPFPRKSSTITTPPFSSEEEQEDDDLIRAYASPGPLPVPPPQNKGSFGKNTVKSD
  ADGTEGSEIEDTDDSPKPAGVAVKTPTEKVEKMFPHRKNVNKPVGGTNVPEMFIKKEELQ
  ELKCADVEDEDWDISSLEEEISLGKKSGKEQKEPPPAKNEPHFAHVLNAWGAFNPKGPKG
  EGLQENESSTLKSSLVTVTDWSDTSDV
• Function: Molecular adapter that recruits protein complexes required for cilium assembly and function to the cilium basal body. At the exit of mitosis, localizes to the basal body and ciliary base of the forming primary cilium where it recruits and activates RAB8A to direct vesicle-mediated transport of proteins to the cilium. Also recruits the BBSome, a complex involved in cilium biogenesis, by bridging it to PCM1 at the centriolar satellites of the cilium. It is also required for the recruitment to the cilium basal body of the intraflagellar transport (IFT) machinery as well as the ciliary appendage proteins CEP164 and NINEIN. Functions as a regulator of Hedgehog signaling both through its role in cilium assembly but also probably through its ability to retain GLI3 within the cytoplasm. It is involved in spermatogenesis through its role in organization of the basal body and assembly of the sperm flagellum. Also indirectly involved in heart development through its function in ciliogenesis.
• Tissue Specificity: Predominantly expressed in testis (at protein level) . Also expressed in fetal brain, adult oocytes and ovary . Expressed in undifferentiated ES cells . In testis, it is specifically expressed in germ cells (at protein level) . Expressed in mature germ cells and secondary spermatocytes, while it is weakly or not expressed in primary spermatocytes .
• Reactome Pathway: Hedgehog 'on' state (R-HSA-5632684)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	moderate	Biomarker	[1]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[1]
Spermatogenic failure 47	DISWJ0Q4	Limited	Autosomal recessive	[2]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Cilium assembly protein DZIP1 (DZIP1) affects the response to substance of Doxorubicin.	[14]
Topotecan	DMP6G8T	Approved	Cilium assembly protein DZIP1 (DZIP1) affects the response to substance of Topotecan.	[14]

5 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 Cilium assembly protein DZIP1 (DZIP1).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Cilium assembly protein DZIP1 (DZIP1).	[6]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Cilium assembly protein DZIP1 (DZIP1).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Cilium assembly protein DZIP1 (DZIP1).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Cilium assembly protein DZIP1 (DZIP1).	[7]

7 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 Cilium assembly protein DZIP1 (DZIP1).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cilium assembly protein DZIP1 (DZIP1).	[5]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Cilium assembly protein DZIP1 (DZIP1).	[8]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Cilium assembly protein DZIP1 (DZIP1).	[9]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide increases the expression of Cilium assembly protein DZIP1 (DZIP1).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Cilium assembly protein DZIP1 (DZIP1).	[12]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Cilium assembly protein DZIP1 (DZIP1).	[13]

References

• [1] Development of a novel approach, the epigenome-based outlier approach, to identify tumor-suppressor genes silenced by aberrant DNA methylation.Cancer Lett. 2012 Sep 28;322(2):204-12. doi: 10.1016/j.canlet.2012.03.016. Epub 2012 Mar 17.
• [2] Homozygous mutations in DZIP1 can induce asthenoteratospermia with severe MMAF. J Med Genet. 2020 Jul;57(7):445-453. doi: 10.1136/jmedgenet-2019-106479. Epub 2020 Feb 12.
• [3] 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.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 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.
• [7] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [8] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [9] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [10] Comparative gene expression analysis of a chronic myelogenous leukemia cell line resistant to cyclophosphamide using oligonucleotide arrays and response to tyrosine kinase inhibitors. Leuk Res. 2007 Nov;31(11):1511-20.
• [11] 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.
• [12] 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.
• [13] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [14] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.