Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJ3AJQU)

• DOT Name: Cell cycle checkpoint control protein RAD9A (RAD9A)
• Synonyms: hRAD9; EC 3.1.11.2; DNA repair exonuclease rad9 homolog A
• Gene Name: RAD9A
• Related Disease:
  Lung adenocarcinoma
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Carcinoma of esophagus
  Chromosomal disorder
  Esophageal cancer
  Klinefelter syndrome
  Lung carcinoma
  Lung neoplasm
  Malignant neoplasm
  Neoplasm of esophagus
  Non-small-cell lung cancer
  Prostate neoplasm
  Skin cancer
  Thyroid tumor
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Lung cancer
• UniProt ID: RAD9A_HUMAN
• PDB ID: 3A1J; 3G65; 3GGR; 6HM5; 6J8Y; 7Z6H; 8GNN; 8JZY
• EC Number: 3.1.11.2
• Pfam ID: PF04139
• Sequence:
  MKCLVTGGNVKVLGKAVHSLSRIGDELYLEPLEDGLSLRTVNSSRSAYACFLFAPLFFQQ
  YQAATPGQDLLRCKILMKSFLSVFRSLAMLEKTVEKCCISLNGRSSRLVVQLHCKFGVRK
  THNLSFQDCESLQAVFDPASCPHMLRAPARVLGEAVLPFSPALAEVTLGIGRGRRVILRS
  YHEEEADSTAKAMVTEMCLGEEDFQQLQAQEGVAITFCLKEFRGLLSFAESANLNLSIHF
  DAPGRPAIFTIKDSLLDGHFVLATLSDTDSHSQDLGSPERHQPVPQLQAHSTPHPDDFAN
  DDIDSYMIAMETTIGNEGSRVLPSISLSPGPQPPKSPGPHSEEEDEAEPSTVPGTPPPKK
  FRSLFFGSILAPVRSPQGPSPVLAEDSEGEG
• 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. RAD9A possesses 3'->5' double stranded DNA exonuclease activity.
• 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

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung adenocarcinoma	DISD51WR	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[4]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[5]
Chromosomal disorder	DISM5BB5	Strong	Biomarker	[6]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[5]
Klinefelter syndrome	DISOUI7W	Strong	Biomarker	[7]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[8]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[8]
Malignant neoplasm	DISS6SNG	Strong	Biomarker	[9]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[5]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[10]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[11]
Skin cancer	DISTM18U	Strong	Genetic Variation	[2]
Thyroid tumor	DISLVKMD	Strong	Altered Expression	[12]
Neoplasm	DISZKGEW	moderate	Biomarker	[8]
Prostate cancer	DISF190Y	moderate	Biomarker	[13]
Prostate carcinoma	DISMJPLE	moderate	Biomarker	[13]
Lung cancer	DISCM4YA	Limited	Altered Expression	[8]

3 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 Cell cycle checkpoint control protein RAD9A (RAD9A).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Cell cycle checkpoint control protein RAD9A (RAD9A).	[20]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Cell cycle checkpoint control protein RAD9A (RAD9A).	[22]

8 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 Cell cycle checkpoint control protein RAD9A (RAD9A).	[15]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Cell cycle checkpoint control protein RAD9A (RAD9A).	[16]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Cell cycle checkpoint control protein RAD9A (RAD9A).	[17]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Cell cycle checkpoint control protein RAD9A (RAD9A).	[18]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 decreases the expression of Cell cycle checkpoint control protein RAD9A (RAD9A).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Cell cycle checkpoint control protein RAD9A (RAD9A).	[21]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Cell cycle checkpoint control protein RAD9A (RAD9A).	[23]
Taurine	DMVW7N3	Investigative	Taurine increases the expression of Cell cycle checkpoint control protein RAD9A (RAD9A).	[24]

References

• [1] Nonsynonymous single nucleotide polymorphisms in DNA damage repair pathways and lung cancer risk.Cancer. 2010 Feb 15;116(4):896-902. doi: 10.1002/cncr.24850.
• [2] The role of RAD9 in tumorigenesis.J Mol Cell Biol. 2011 Feb;3(1):39-43. doi: 10.1093/jmcb/mjq039.
• [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] The cell cycle checkpoint gene Rad9 is a novel oncogene activated by 11q13 amplification and DNA methylation in breast cancer.Cancer Res. 2005 Oct 1;65(19):8646-54. doi: 10.1158/0008-5472.CAN-04-4243.
• [5] Knockdown of Rad9A enhanced DNA damage induced by trichostatin A in esophageal cancer cells.Tumour Biol. 2016 Jan;37(1):963-70. doi: 10.1007/s13277-015-3879-z. Epub 2015 Aug 12.
• [6] Human Rad9 is required for the activation of S-phase checkpoint and the maintenance of chromosomal stability.Genes Cells. 2005 Apr;10(4):287-95. doi: 10.1111/j.1365-2443.2005.00840.x.
• [7] Identification and characterization of a novel nuclear structure containing members of the homologous recombination and DNA damage response pathways.Cancer Genet. 2018 Dec;228-229:98-109. doi: 10.1016/j.cancergen.2018.10.003. Epub 2018 Oct 18.
• [8] Resveratrol induced premature senescence and inhibited epithelial-mesenchymal transition of cancer cells via induction of tumor suppressor Rad9.PLoS One. 2019 Jul 16;14(7):e0219317. doi: 10.1371/journal.pone.0219317. eCollection 2019.
• [9] Reduced mRNA and protein expression of the genomic caretaker RAD9A in primary fibroblasts of individuals with childhood and independent second cancer.PLoS One. 2011;6(10):e25750. doi: 10.1371/journal.pone.0025750. Epub 2011 Oct 3.
• [10] DNA damage sensor protein hRad9, a novel molecular target for lung cancer treatment.Oncol Rep. 2008 Nov;20(5):1047-52.
• [11] Rad9 has a functional role in human prostate carcinogenesis.Cancer Res. 2008 Mar 1;68(5):1267-74. doi: 10.1158/0008-5472.CAN-07-2304.
• [12] Diagnostic and prognostic value of cell-cycle regulatory genes in malignant thyroid neoplasms.World J Surg. 2006 May;30(5):767-74. doi: 10.1007/s00268-005-0308-2.
• [13] RAD9A promotes metastatic phenotypes through transcriptional regulation of anterior gradient 2 (AGR2).Carcinogenesis. 2019 Mar 12;40(1):164-172. doi: 10.1093/carcin/bgy131.
• [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] Caffeine disrupts ataxia telangiectasia mutated gene-related pathways and exacerbates acetaminophen toxicity in human fetal immortalized hepatocytes. Toxicology. 2021 Jun 15;457:152811. doi: 10.1016/j.tox.2021.152811. Epub 2021 May 7.
• [16] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [17] Activation of the p38 MAPK/Akt/ERK1/2 signal pathways is required for the protein stabilization of CDC6 and cyclin D1 in low-dose arsenite-induced cell proliferation. J Cell Biochem. 2010 Dec 15;111(6):1546-55. doi: 10.1002/jcb.22886.
• [18] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [19] Global expression profiling of theophylline response genes in macrophages: evidence of airway anti-inflammatory regulation. Respir Res. 2005 Aug 8;6(1):89. doi: 10.1186/1465-9921-6-89.
• [20] Bisphenol-A impairs cellular function and alters DNA methylation of stress pathway genes in first trimester trophoblast cells. Reprod Toxicol. 2018 Dec;82:72-79.
• [21] MCM-2 is a therapeutic target of Trichostatin A in colon cancer cells. Toxicol Lett. 2013 Jul 31;221(1):23-30. doi: 10.1016/j.toxlet.2013.05.643. Epub 2013 Jun 13.
• [22] 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.
• [23] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [24] Taurine-responsive genes related to signal transduction as identified by cDNA microarray analyses of HepG2 cells. J Med Food. 2006 Spring;9(1):33-41. doi: 10.1089/jmf.2006.9.33.