Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWMV16B)

• DOT Name: Holliday junction recognition protein (HJURP)
• Synonyms: 14-3-3-associated AKT substrate; Fetal liver-expressing gene 1 protein; Up-regulated in lung cancer 9
• Gene Name: HJURP
• Related Disease:
  Metastatic malignant neoplasm
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Endometrial cancer
  Endometrial carcinoma
  Hepatocellular carcinoma
  Lung cancer
  Lung carcinoma
  Migraine disorder
  Non-small-cell lung cancer
  Prostate cancer
  Prostate carcinoma
  Urinary bladder cancer
  Urinary bladder neoplasm
  Chronic obstructive pulmonary disease
  Neoplasm
  Adult glioblastoma
  Glioblastoma multiforme
  Clear cell renal carcinoma
• UniProt ID: HJURP_HUMAN
• PDB ID: 3R45
• Pfam ID: PF12347 ; PF12346 ; PF10384
• Sequence:
  MLGTLRAMEGEDVEDDQLLQKLRASRRRFQRRMQRLIEKYNQPFEDTPVVQMATLTYETP
  QGLRIWGGRLIKERNEGEIQDSSMKPADRTDGSVQAAAWGPELPSHRTVLGADSKSGEVD
  ATSDQEESVAWALAPAVPQSPLKNELRRKYLTQVDILLQGAEYFECAGNRAGRDVRVTPL
  PSLASPAVPAPGYCSRISRKSPGDPAKPASSPREWDPLHPSSTDMALVPRNDSLSLQETS
  SSSFLSSQPFEDDDICNVTISDLYAGMLHSMSRLLSTKPSSIISTKTFIMQNWNSRRRHR
  YKSRMNKTYCKGARRSQRSSKENFIPCSEPVKGTGALRDCKNVLDVSCRKTGLKLEKAFL
  EVNRPQIHKLDPSWKERKVTPSKYSSLIYFDSSATYNLDEENRFRTLKWLISPVKIVSRP
  TIRQGHGENRQREIEIRFDQLHREYCLSPRNQPRRMCLPDSWAMNMYRGGPASPGGLQGL
  ETRRLSLPSSKAKAKSLSEAFENLGKRSLEAGRCLPKSDSSSSLPKTNPTHSATRPQQTS
  DLHVQGNSSGIFRKSVSPSKTLSVPDKEVPGHGRNRYDEIKEEFDKLHQKYCLKSPGQMT
  VPLCIGVSTDKASMEVRYQTEGFLGKLNPDPHFQGFQKLPSSPLGCRKSLLGSTAIEAPS
  STCVARAITRDGTRDHQFPAKRPRLSEPQGSGRQGNSLGASDGVDNTVRPGDQGSSSQPN
  SEERGENTSYRMEEKSDFMLEKLETKSV
• Function: Centromeric protein that plays a central role in the incorporation and maintenance of histone H3-like variant CENPA at centromeres. Acts as a specific chaperone for CENPA and is required for the incorporation of newly synthesized CENPA molecules into nucleosomes at replicated centromeres. Prevents CENPA-H4 tetramerization and prevents premature DNA binding by the CENPA-H4 tetramer. Directly binds Holliday junctions.
• Tissue Specificity: According to PubMed:17256767, highly expressed in the thymus with lower levels in the placenta, small intestine, liver, skeletal muscle, and colon. According to PubMed:17823411, highly expressed in testis, and at a relatively lower level in thymus and bone marrow. Significantly overexpressed in many lung cancer samples, compared with normal lung.
• Reactome Pathway: Deposition of new CENPA-containing nucleosomes at the centromere (R-HSA-606279)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Metastatic malignant neoplasm	DIS86UK6	Definitive	Biomarker	[1]
Bladder cancer	DISUHNM0	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[5]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[1]
Lung cancer	DISCM4YA	Strong	Altered Expression	[6]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[6]
Migraine disorder	DISFCQTG	Strong	Genetic Variation	[7]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[6]
Prostate cancer	DISF190Y	Strong	Altered Expression	[8]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[8]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[2]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[2]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Biomarker	[9]
Neoplasm	DISZKGEW	moderate	Altered Expression	[8]
Adult glioblastoma	DISVP4LU	Disputed	Biomarker	[10]
Glioblastoma multiforme	DISK8246	Disputed	Biomarker	[10]
Clear cell renal carcinoma	DISBXRFJ	Limited	Altered Expression	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Holliday junction recognition protein (HJURP).	[12]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Holliday junction recognition protein (HJURP).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Holliday junction recognition protein (HJURP).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Holliday junction recognition protein (HJURP).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Holliday junction recognition protein (HJURP).	[16]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Holliday junction recognition protein (HJURP).	[17]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Holliday junction recognition protein (HJURP).	[18]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Holliday junction recognition protein (HJURP).	[20]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Holliday junction recognition protein (HJURP).	[20]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Holliday junction recognition protein (HJURP).	[21]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Holliday junction recognition protein (HJURP).	[22]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Holliday junction recognition protein (HJURP).	[23]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Holliday junction recognition protein (HJURP).	[24]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Holliday junction recognition protein (HJURP).	[25]
Lucanthone	DMZLBUO	Approved	Lucanthone decreases the expression of Holliday junction recognition protein (HJURP).	[26]
Methamphetamine	DMPM4SK	Approved	Methamphetamine decreases the expression of Holliday junction recognition protein (HJURP).	[27]
Palbociclib	DMD7L94	Approved	Palbociclib decreases the expression of Holliday junction recognition protein (HJURP).	[28]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Holliday junction recognition protein (HJURP).	[30]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Holliday junction recognition protein (HJURP).	[32]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Holliday junction recognition protein (HJURP).	[34]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Holliday junction recognition protein (HJURP).	[35]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Holliday junction recognition protein (HJURP).	[18]

5 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 Holliday junction recognition protein (HJURP).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Holliday junction recognition protein (HJURP).	[29]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Holliday junction recognition protein (HJURP).	[31]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Holliday junction recognition protein (HJURP).	[33]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Holliday junction recognition protein (HJURP).	[33]

References

• [1] HJURP Promotes Epithelial-to-Mesenchymal Transition via Upregulating SPHK1 in Hepatocellular Carcinoma.Int J Biol Sci. 2019 May 7;15(6):1139-1147. doi: 10.7150/ijbs.30904. eCollection 2019.
• [2] Silencing of HJURP induces dysregulation of cell cycle and ROS metabolism in bladder cancer cells via PPAR-SIRT1 feedback loop.J Cancer. 2017 Jul 20;8(12):2282-2295. doi: 10.7150/jca.19967. eCollection 2017.
• [3] Misregulation of Scm3p/HJURP causes chromosome instability in Saccharomyces cerevisiae and human cells.PLoS Genet. 2011 Sep;7(9):e1002303. doi: 10.1371/journal.pgen.1002303. Epub 2011 Sep 29.
• [4] The expression level of HJURP has an independent prognostic impact and predicts the sensitivity to radiotherapy in breast cancer.Breast Cancer Res. 2010;12(2):R18. doi: 10.1186/bcr2487. Epub 2010 Mar 8.
• [5] Identification of key pathways and genes in endometrial cancer using bioinformatics analyses.Oncol Lett. 2019 Jan;17(1):897-906. doi: 10.3892/ol.2018.9667. Epub 2018 Nov 5.
• [6] Clinical verification of plasma messenger RNA as novel noninvasive biomarker identified through bioinformatics analysis for lung cancer.Oncotarget. 2017 Jul 4;8(27):43978-43989. doi: 10.18632/oncotarget.16701.
• [7] Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine.Nat Genet. 2016 Aug;48(8):856-66. doi: 10.1038/ng.3598. Epub 2016 Jun 20.
• [8] Upregulation of Holliday junction recognition protein predicts poor prognosis and biochemical recurrence in patients with prostate cancer.Oncol Lett. 2019 Dec;18(6):6697-6703. doi: 10.3892/ol.2019.11061. Epub 2019 Nov 5.
• [9] A candidate gene identification strategy utilizing mouse to human big-data mining: "3R-tenet" in COPD genetic research.Respir Res. 2018 Jun 6;19(1):92. doi: 10.1186/s12931-018-0795-y.
• [10] HJURP knockdown disrupts clonogenic capacity and increases radiation-induced cell death of glioblastoma cells.Cancer Gene Ther. 2020 May;27(5):319-329. doi: 10.1038/s41417-019-0103-0. Epub 2019 May 29.
• [11] Identification of key genes involved in the metastasis of clear cell renal cell carcinoma.Oncol Lett. 2019 May;17(5):4321-4328. doi: 10.3892/ol.2019.10130. Epub 2019 Mar 8.
• [12] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [13] Inter-laboratory comparison of human renal proximal tubule (HK-2) transcriptome alterations due to Cyclosporine A exposure and medium exhaustion. Toxicol In Vitro. 2009 Apr;23(3):486-99.
• [14] Effect of retinoic acid on gene expression in human conjunctival epithelium: secretory phospholipase A2 mediates retinoic acid induction of MUC16. Invest Ophthalmol Vis Sci. 2005 Nov;46(11):4050-61.
• [15] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [16] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [17] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [18] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [19] 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.
• [20] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [21] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [22] 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.
• [23] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [24] In vitro effects of aldehydes present in tobacco smoke on gene expression in human lung alveolar epithelial cells. Toxicol In Vitro. 2013 Apr;27(3):1072-81.
• [25] 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.
• [26] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [27] Methamphetamine alters the normal progression by inducing cell cycle arrest in astrocytes. PLoS One. 2014 Oct 7;9(10):e109603.
• [28] Cdk4/6 inhibition induces epithelial-mesenchymal transition and enhances invasiveness in pancreatic cancer cells. Mol Cancer Ther. 2012 Oct;11(10):2138-48. doi: 10.1158/1535-7163.MCT-12-0562. Epub 2012 Aug 6.
• [29] 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.
• [30] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [31] 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.
• [32] 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.
• [33] 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.
• [34] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [35] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.