Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY1XON9)

• DOT Name: Checkpoint protein HUS1 (HUS1)
• Synonyms: hHUS1
• Gene Name: HUS1
• Related Disease:
  Hepatocellular carcinoma
  Neoplasm
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Epithelial ovarian cancer
  Ovarian cancer
  Ovarian neoplasm
  Thyroid gland papillary carcinoma
• UniProt ID: HUS1_HUMAN
• PDB ID: 3A1J; 3G65; 3GGR; 6J8Y; 7Z6H; 8GNN
• Pfam ID: PF04005
• Sequence:
  MKFRAKIVDGACLNHFTRISNMIAKLAKTCTLRISPDKLNFILCDKLANGGVSMWCELEQ
  ENFFNEFQMEGVSAENNEIYLELTSENLSRALKTAQNARALKIKLTNKHFPCLTVSVELL
  SMSSSSRIVTHDIPIKVIPRKLWKDLQEPVVPDPDVSIYLPVLKTMKSVVEKMKNISNHL
  VIEANLDGELNLKIETELVCVTTHFKDLGNPPLASESTHEDRNVEHMAEVHIDIRKLLQF
  LAGQQVNPTKALCNIVNNKMVHFDLLHEDVSLQYFIPALS
• Function: Component of the 9-1-1 cell-cycle checkpoint response complex that plays a major role in DNA repair. The 9-1-1 complex is recruited to DNA lesion upon damage by the RAD17-replication factor C (RFC) clamp loader complex. Acts then as a sliding clamp platform on DNA for several proteins involved in long-patch base excision repair (LP-BER). The 9-1-1 complex stimulates DNA polymerase beta (POLB) activity by increasing its affinity for the 3'-OH end of the primer-template and stabilizes POLB to those sites where LP-BER proceeds; endonuclease FEN1 cleavage activity on substrates with double, nick, or gap flaps of distinct sequences and lengths; and DNA ligase I (LIG1) on long-patch base excision repair substrates. The 9-1-1 complex is necessary for the recruitment of RHNO1 to sites of double-stranded breaks (DSB) occurring during the S phase.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway: Cellular senescence (hsa04218)
• Reactome Pathway:
  HDR through Single Strand Annealing (SSA) (R-HSA-5685938)
  Processing of DNA double-strand break ends (R-HSA-5693607)
  Presynaptic phase of homologous DNA pairing and strand exchange (R-HSA-5693616)
  Regulation of TP53 Activity through Phosphorylation (R-HSA-6804756)
  G2/M DNA damage checkpoint (R-HSA-69473)
  Impaired BRCA2 binding to RAD51 (R-HSA-9709570)
  Activation of ATR in response to replication stress (R-HSA-176187)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Limited	Genetic Variation	[2]
Breast cancer	DIS7DPX1	Limited	Biomarker	[3]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[3]
Epithelial ovarian cancer	DIS56MH2	Limited	Genetic Variation	[2]
Ovarian cancer	DISZJHAP	Limited	Genetic Variation	[2]
Ovarian neoplasm	DISEAFTY	Limited	Genetic Variation	[2]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Genetic Variation	[4]

12 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 Checkpoint protein HUS1 (HUS1).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Checkpoint protein HUS1 (HUS1).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Checkpoint protein HUS1 (HUS1).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Checkpoint protein HUS1 (HUS1).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Checkpoint protein HUS1 (HUS1).	[10]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Checkpoint protein HUS1 (HUS1).	[11]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Checkpoint protein HUS1 (HUS1).	[12]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Checkpoint protein HUS1 (HUS1).	[13]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Checkpoint protein HUS1 (HUS1).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Checkpoint protein HUS1 (HUS1).	[16]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 decreases the expression of Checkpoint protein HUS1 (HUS1).	[17]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Checkpoint protein HUS1 (HUS1).	[18]

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 Checkpoint protein HUS1 (HUS1).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Checkpoint protein HUS1 (HUS1).	[15]

References

• [1] HUS1 checkpoint clamp component (HUS1) is a potential tumor suppressor in primary hepatocellular carcinoma.Mol Carcinog. 2019 Jan;58(1):76-87. doi: 10.1002/mc.22908. Epub 2018 Sep 19.
• [2] Low penetrance alleles as risk modifiers in familial and sporadic breast cancer.Fam Cancer. 2012 Dec;11(4):629-36. doi: 10.1007/s10689-012-9563-1.
• [3] Over expression of hRad9 protein correlates with reduced chemosensitivity in breast cancer with administration of neoadjuvant chemotherapy.Sci Rep. 2014 Dec 18;4:7548. doi: 10.1038/srep07548.
• [4] Common genetic variants related to genomic integrity and risk of papillary thyroid cancer.Carcinogenesis. 2011 Aug;32(8):1231-7. doi: 10.1093/carcin/bgr100. Epub 2011 Jun 3.
• [5] Downregulation of homologous recombination DNA repair genes by HDAC inhibition in prostate cancer is mediated through the E2F1 transcription factor. PLoS One. 2010 Jun 18;5(6):e11208. doi: 10.1371/journal.pone.0011208.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [11] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [12] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [15] 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.
• [16] 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.
• [17] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [18] Genome-wide impact of androgen receptor trapped clone-27 loss on androgen-regulated transcription in prostate cancer cells. Cancer Res. 2009 Apr 1;69(7):3140-7. doi: 10.1158/0008-5472.CAN-08-3738. Epub 2009 Mar 24.