Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT886MA8)

• DOT Name: Cell cycle checkpoint protein RAD1 (RAD1)
• Synonyms: hRAD1; Rad1-like DNA damage checkpoint protein
• Gene Name: RAD1
• Related Disease:
  Congenital alveolar dysplasia
  Immunodeficiency
  Mantle cell lymphoma
  Myopia
  Type-1/2 diabetes
  Xeroderma pigmentosum group F
  B-cell lymphoma
  Breast cancer
  Breast carcinoma
  Neoplasm
• UniProt ID: RAD1_HUMAN
• PDB ID: 3A1J; 3G65; 3GGR; 6J8Y; 7Z6H; 8GNN
• Pfam ID: PF02144
• Sequence:
  MPLLTQQIQDEDDQYSLVASLDNVRNLSTILKAIHFREHATCFATKNGIKVTVENAKCVQ
  ANAFIQAGIFQEFKVQEESVTFRINLTVLLDCLSIFGSSPMPGTLTALRMCYQGYGYPLM
  LFLEEGGVVTVCKINTQEPEETLDFDFCSTNVINKIILQSEGLREAFSELDMTSEVLQIT
  MSPDKPYFRLSTFGNAGSSHLDYPKDSDLMEAFHCNQTQVNRYKISLLKPSTKALVLSCK
  VSIRTDNRGFLSLQYMIRNEDGQICFVEYYCCPDEEVPESES
• 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: Expressed in testis, uterus, bladder, spleen, ovaries, lung, brain and muscle (at protein level).
• 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

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital alveolar dysplasia	DIS1IYUN	Strong	Biomarker	[1]
Immunodeficiency	DIS093I0	Strong	Biomarker	[2]
Mantle cell lymphoma	DISFREOV	Strong	Biomarker	[3]
Myopia	DISK5S60	Strong	Biomarker	[4]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[5]
Xeroderma pigmentosum group F	DISRKRYY	Strong	Biomarker	[6]
B-cell lymphoma	DISIH1YQ	Limited	Biomarker	[7]
Breast cancer	DIS7DPX1	Limited	Biomarker	[8]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[8]
Neoplasm	DISZKGEW	Limited	Altered Expression	[9]

10 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 Cell cycle checkpoint protein RAD1 (RAD1).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cell cycle checkpoint protein RAD1 (RAD1).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Cell cycle checkpoint protein RAD1 (RAD1).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cell cycle checkpoint protein RAD1 (RAD1).	[13]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Cell cycle checkpoint protein RAD1 (RAD1).	[14]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Cell cycle checkpoint protein RAD1 (RAD1).	[15]
Arecoline	DMFJZK3	Phase 1	Arecoline decreases the expression of Cell cycle checkpoint protein RAD1 (RAD1).	[16]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Cell cycle checkpoint protein RAD1 (RAD1).	[17]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Cell cycle checkpoint protein RAD1 (RAD1).	[18]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID increases the expression of Cell cycle checkpoint protein RAD1 (RAD1).	[19]

References

• [1] Disruption of the Rad9/Rad1/Hus1 (9-1-1) complex leads to checkpoint signaling and replication defects.Oncogene. 2004 Jul 22;23(33):5586-93. doi: 10.1038/sj.onc.1207753.
• [2] Mouse models of mantle cell lymphoma, complex changes in gene expression and phenotype of engrafted MCL cells: implications for preclinical research.Lab Invest. 2014 Jul;94(7):806-17. doi: 10.1038/labinvest.2014.61. Epub 2014 May 26.
• [3] The therapeutic effectiveness of (177)Lu-lilotomab in B-cell non-Hodgkin lymphoma involves modulation of G2/M cell cycle arrest.Leukemia. 2020 May;34(5):1315-1328. doi: 10.1038/s41375-019-0677-4. Epub 2019 Dec 13.
• [4] Relationship between Aquaporin-1 Protein Expression and Choroidal Thickness during the Recovery of Form-deprivation Myopia in Guinea Pigs.Curr Eye Res. 2020 Jun;45(6):705-712. doi: 10.1080/02713683.2019.1689275. Epub 2019 Nov 19.
• [5] Analysis of trinucleotide-repeat combination polymorphism at the rad gene in patients with type 2 diabetes mellitus.Metabolism. 1999 Feb;48(2):173-5. doi: 10.1016/s0026-0495(99)90029-x.
• [6] Xeroderma pigmentosum group F caused by a defect in a structure-specific DNA repair endonuclease.Cell. 1996 Sep 6;86(5):811-22. doi: 10.1016/s0092-8674(00)80155-5.
• [7] Targeting B-cell malignancies with the beta-emitting anti-CD37 radioimmunoconjugate (177)Lu-NNV003.Eur J Nucl Med Mol Imaging. 2019 Oct;46(11):2311-2321. doi: 10.1007/s00259-019-04417-1. Epub 2019 Jul 15.
• [8] 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.
• [9] Deletion of 11q23 and cyclin D1 overexpression are frequent aberrations in parathyroid adenomas.Am J Pathol. 2001 Apr;158(4):1355-62. doi: 10.1016/S0002-9440(10)64086-2.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] 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.
• [12] 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.
• [13] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [14] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [15] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [16] Characterization of arecoline-induced effects on cytotoxicity in normal human gingival fibroblasts by global gene expression profiling. Toxicol Sci. 2007 Nov;100(1):66-74.
• [17] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [18] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.
• [19] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.