Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1I93DT)

• DOT Name: Cell cycle checkpoint protein RAD17 (RAD17)
• Synonyms: hRad17; RF-C/activator 1 homolog
• Gene Name: RAD17
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Carcinoma
  Esophageal squamous cell carcinoma
  Fibrosarcoma
  Head and neck cancer
  Head and neck carcinoma
  Head and neck neoplasm
  Head-neck squamous cell carcinoma
  Lung cancer
  Lung carcinoma
  Neoplasm
  Oral cancer
  Pancreatic cancer
  Seminoma
  Squamous cell carcinoma
  Lung neoplasm
  Non-small-cell lung cancer
  Warsaw breakage syndrome
• UniProt ID: RAD17_HUMAN
• PDB ID: 7Z6H; 8GNN
• Pfam ID: PF03215
• Sequence:
  MSKTFLRPKVSSTKVTDWVDPSFDDFLECSGVSTITATSLGVNNSSHRRKNGPSTLESSR
  FPARKRGNLSSLEQIYGLENSKEYLSENEPWVDKYKPETQHELAVHKKKIEEVETWLKAQ
  VLERQPKQGGSILLITGPPGCGKTTTLKILSKEHGIQVQEWINPVLPDFQKDDFKGMFNT
  ESSFHMFPYQSQIAVFKEFLLRATKYNKLQMLGDDLRTDKKIILVEDLPNQFYRDSHTLH
  EVLRKYVRIGRCPLIFIISDSLSGDNNQRLLFPKEIQEECSISNISFNPVAPTIMMKFLN
  RIVTIEANKNGGKITVPDKTSLELLCQGCSGDIRSAINSLQFSSSKGENNLRPRKKGMSL
  KSDAVLSKSKRRKKPDRVFENQEVQAIGGKDVSLFLFRALGKILYCKRASLTELDSPRLP
  SHLSEYERDTLLVEPEEVVEMSHMPGDLFNLYLHQNYIDFFMEIDDIVRASEFLSFADIL
  SGDWNTRSLLREYSTSIATRGVMHSNKARGYAHCQGGGSSFRPLHKPQWFLINKKYRENC
  LAAKALFPDFCLPALCLQTQLLPYLALLTIPMRNQAQISFIQDIGRLPLKRHFGRLKMEA
  LTDREHGMIDPDSGDEAQLNGGHSAEESLGEPTQATVPETWSLPLSQNSASELPASQPQP
  FSAQGDMEENIIIEDYESDGT
• Function: Essential for sustained cell growth, maintenance of chromosomal stability, and ATR-dependent checkpoint activation upon DNA damage. Has a weak ATPase activity required for binding to chromatin. Participates in the recruitment of the 9-1-1 (RAD1-RAD9-HUS1) complex and RHNO1 onto chromatin, and in CHEK1 activation. May also serve as a sensor of DNA replication progression, and may be involved in homologous recombination.
• Tissue Specificity: Overexpressed in various cancer cell lines and in colon carcinoma (at protein level). Isoform 2 and isoform 3 are the most abundant isoforms in non irradiated cells (at protein level). Ubiquitous at low levels. Highly expressed in testis, where it is expressed within the germinal epithelium of the seminiferous tubuli. Weakly expressed in seminomas (testicular tumors).
• 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

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Carcinoma	DISH9F1N	Strong	Biomarker	[3]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Genetic Variation	[4]
Fibrosarcoma	DISWX7MU	Strong	Altered Expression	[5]
Head and neck cancer	DISBPSQZ	Strong	Altered Expression	[6]
Head and neck carcinoma	DISOU1DS	Strong	Altered Expression	[6]
Head and neck neoplasm	DIS1OB2G	Strong	Biomarker	[6]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Altered Expression	[7]
Lung cancer	DISCM4YA	Strong	Biomarker	[8]
Lung carcinoma	DISTR26C	Strong	Biomarker	[8]
Neoplasm	DISZKGEW	Strong	Biomarker	[9]
Oral cancer	DISLD42D	Strong	Biomarker	[10]
Pancreatic cancer	DISJC981	Strong	Biomarker	[11]
Seminoma	DIS3J8LJ	Strong	Genetic Variation	[12]
Squamous cell carcinoma	DISQVIFL	moderate	Biomarker	[7]
Lung neoplasm	DISVARNB	Limited	Altered Expression	[1]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Altered Expression	[1]
Warsaw breakage syndrome	DIS1AE2E	Limited	Biomarker	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Cell cycle checkpoint protein RAD17 (RAD17).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cell cycle checkpoint protein RAD17 (RAD17).	[15]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Cell cycle checkpoint protein RAD17 (RAD17).	[16]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Cell cycle checkpoint protein RAD17 (RAD17).	[17]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of Cell cycle checkpoint protein RAD17 (RAD17).	[18]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Cell cycle checkpoint protein RAD17 (RAD17).	[20]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Cell cycle checkpoint protein RAD17 (RAD17).	[21]
Piroxicam	DMTK234	Approved	Piroxicam increases the expression of Cell cycle checkpoint protein RAD17 (RAD17).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Cell cycle checkpoint protein RAD17 (RAD17).	[23]
OXYBENZONE	DMMZYX6	Investigative	OXYBENZONE increases the expression of Cell cycle checkpoint protein RAD17 (RAD17).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Cell cycle checkpoint protein RAD17 (RAD17).	[19]

References

• [1] Overexpression of Hrad17 gene in non-small cell lung cancers correlated with lymph node metastasis.Lung Cancer. 2001 Oct;34(1):47-52. doi: 10.1016/s0169-5002(01)00223-9.
• [2] Regulation of Rad17 protein turnover unveils an impact of Rad17-APC cascade in breast carcinogenesis and treatment.J Biol Chem. 2013 Jun 21;288(25):18134-45. doi: 10.1074/jbc.M113.456962. Epub 2013 May 1.
• [3] HRad17, a human homologue of the Schizosaccharomyces pombe checkpoint gene rad17, is overexpressed in colon carcinoma.Cancer Res. 1999 May 1;59(9):2023-8.
• [4] The noncoding function of NELFA mRNA promotes the development of oesophageal squamous cell carcinoma by regulating the Rad17-RFC2-5 complex.Mol Oncol. 2020 Mar;14(3):611-624. doi: 10.1002/1878-0261.12619. Epub 2020 Jan 28.
• [5] hRAD17, a structural homolog of the Schizosaccharomyces pombe RAD17 cell cycle checkpoint gene, stimulates p53 accumulation.Oncogene. 1999 Mar 4;18(9):1689-99. doi: 10.1038/sj.onc.1202469.
• [6] Downregulation of RAD17 in head and neck cancer.Head Neck. 2008 Jan;30(1):35-42. doi: 10.1002/hed.20660.
• [7] The miR-205-5p/BRCA1/RAD17 Axis Promotes Genomic Instability in Head and Neck Squamous Cell Carcinomas.Cancers (Basel). 2019 Sep 11;11(9):1347. doi: 10.3390/cancers11091347.
• [8] Human Rad17 is phosphorylated upon DNA damage and also overexpressed in primary non-small cell lung cancer tissues.Cancer Res. 2001 Oct 15;61(20):7417-21.
• [9] Chemogenetic profiling identifies RAD17 as synthetically lethal with checkpoint kinase inhibition.Oncotarget. 2015 Nov 3;6(34):35755-69. doi: 10.18632/oncotarget.5928.
• [10] Genomic instability and tumor-specific alterations in oral squamous cell carcinomas assessed by inter-(simple sequence repeat) PCR.Clin Cancer Res. 2003 Mar;9(3):1057-62.
• [11] Depletion of RAD17 sensitizes pancreatic cancer cells to gemcitabine.J Cell Sci. 2013 Aug 1;126(Pt 15):3380-9. doi: 10.1242/jcs.124768. Epub 2013 May 17.
• [12] Human and mouse RAD17 genes: identification, localization, genomic structure and histological expression pattern in normal testis and seminoma.Hum Genet. 1999 Jul-Aug;105(1-2):17-27. doi: 10.1007/s004399900067.
• [13] Warsaw breakage syndrome DDX11 helicase acts jointly with RAD17 in the repair of bulky lesions and replication through abasic sites.Proc Natl Acad Sci U S A. 2018 Aug 14;115(33):8412-8417. doi: 10.1073/pnas.1803110115. Epub 2018 Jul 30.
• [14] 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.
• [15] 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.
• [16] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [17] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [18] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [19] 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.
• [20] Gene expression profile of human lymphoid CEM cells sensitive and resistant to glucocorticoid-evoked apoptosis. Genomics. 2003 Jun;81(6):543-55.
• [21] Effects of acute ethanol treatment on NCCIT cells and NCCIT cell-derived embryoid bodies (EBs). Toxicol In Vitro. 2010 Sep;24(6):1696-704. doi: 10.1016/j.tiv.2010.05.017. Epub 2010 May 26.
• [22] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [23] 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.
• [24] Chromatin modifiers: A new class of pollutants with potential epigenetic effects revealed by in vitro assays and transcriptomic analyses. Toxicology. 2023 Jan 15;484:153413. doi: 10.1016/j.tox.2022.153413. Epub 2022 Dec 26.