Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK717YY)

• DOT Name: DNA repair protein XRCC3
• Synonyms: X-ray repair cross-complementing protein 3
• Gene Name: XRCC3
• UniProt ID: XRCC3_HUMAN
• Pfam ID: PF08423
• Sequence:
  MDLDLLDLNPRIIAAIKKAKLKSVKEVLHFSGPDLKRLTNLSSPEVWHLLRTASLHLRGS
  SILTALQLHQQKERFPTQHQRLSLGCPVLDALLRGGLPLDGITELAGRSSAGKTQLALQL
  CLAVQFPRQHGGLEAGAVYICTEDAFPHKRLQQLMAQQPRLRTDVPGELLQKLRFGSQIF
  IEHVADVDTLLECVNKKVPVLLSRGMARLVVIDSVAAPFRCEFDSQASAPRARHLQSLGA
  TLRELSSAFQSPVLCINQVTEAMEEQGAAHGPLGFWDERVSPALGITWANQLLVRLLADR
  LREEEAALGCPARTLRVLSAPHLPPSSCSYTISAEGVRGTPGTQSH
• Function: Involved in the homologous recombination repair (HRR) pathway of double-stranded DNA, thought to repair chromosomal fragmentation, translocations and deletions. Part of the RAD51 paralog protein complex CX3 which acts in the BRCA1-BRCA2-dependent HR pathway. Upon DNA damage, CX3 acts downstream of RAD51 recruitment; the complex binds predominantly to the intersection of the four duplex arms of the Holliday junction (HJ) and to junctions of replication forks. Involved in HJ resolution and thus in processing HR intermediates late in the DNA repair process; the function may be linked to the CX3 complex and seems to involve GEN1 during mitotic cell cycle progression. Part of a PALB2-scaffolded HR complex containing BRCA2 and RAD51C and which is thought to play a role in DNA repair by HR. Plays a role in regulating mitochondrial DNA copy number under conditions of oxidative stress in the presence of RAD51 and RAD51C.
• KEGG Pathway: Homologous recombi.tion (hsa03440)
• Reactome Pathway:
  Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA) (R-HSA-5693554)
  Resolution of D-loop Structures through Holliday Junction Intermediates (R-HSA-5693568)
  Homologous DNA Pairing and Strand Exchange (R-HSA-5693579)
  HDR through Homologous Recombination (HRR) (R-HSA-5685942)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	DNA repair protein XRCC3 affects the response to substance of Arsenic.	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of DNA repair protein XRCC3.	[1]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of DNA repair protein XRCC3.	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of DNA repair protein XRCC3.	[3]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of DNA repair protein XRCC3.	[1]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of DNA repair protein XRCC3.	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of DNA repair protein XRCC3.	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of DNA repair protein XRCC3.	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of DNA repair protein XRCC3.	[7]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of DNA repair protein XRCC3.	[7]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of DNA repair protein XRCC3.	[8]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of DNA repair protein XRCC3.	[9]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of DNA repair protein XRCC3.	[10]
Aspirin	DM672AH	Approved	Aspirin increases the expression of DNA repair protein XRCC3.	[11]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of DNA repair protein XRCC3.	[12]
Beta-carotene	DM0RXBT	Approved	Beta-carotene increases the expression of DNA repair protein XRCC3.	[13]
Camptothecin	DM6CHNJ	Phase 3	Camptothecin decreases the expression of DNA repair protein XRCC3.	[14]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of DNA repair protein XRCC3.	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of DNA repair protein XRCC3.	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of DNA repair protein XRCC3.	[17]
Dimethylformamide	DML6O4N	Investigative	Dimethylformamide increases the expression of DNA repair protein XRCC3.	[18]

References

• [1] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [2] Exploring pradimicin-IRD antineoplastic mechanisms and related DNA repair pathways. Chem Biol Interact. 2023 Feb 1;371:110342. doi: 10.1016/j.cbi.2023.110342. Epub 2023 Jan 10.
• [3] 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.
• [4] 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.
• [5] Arsenic trioxide induces different gene expression profiles of genes related to growth and apoptosis in glioma cells dependent on the p53 status. Mol Biol Rep. 2008 Sep;35(3):421-9.
• [6] Pro-oxidant induced DNA damage in human lymphoblastoid cells: homeostatic mechanisms of genotoxic tolerance. Toxicol Sci. 2012 Aug;128(2):387-97. doi: 10.1093/toxsci/kfs152. Epub 2012 Apr 26.
• [7] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [8] Cannabidiol-induced transcriptomic changes and cellular senescence in human Sertoli cells. Toxicol Sci. 2023 Feb 17;191(2):227-238. doi: 10.1093/toxsci/kfac131.
• [9] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [10] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [11] Aspirin and alterations in DNA repair proteins in the SW480 colorectal cancer cell line. Oncol Rep. 2010 Jul;24(1):37-46. doi: 10.3892/or_00000826.
• [12] New role for nuclear hormone receptors and coactivators in regulation of BRCA1-mediated DNA repair in breast cancer cell lines. Breast Cancer Res. 2006;8(1):R1. doi: 10.1186/bcr1362. Epub 2005 Dec 9.
• [13] Beta-carotene and apocarotenals promote retinoid signaling in BEAS-2B human bronchioepithelial cells. Arch Biochem Biophys. 2006 Nov 1;455(1):48-60.
• [14] Myristicin from nutmeg induces apoptosis via the mitochondrial pathway and down regulates genes of the DNA damage response pathways in human leukaemia K562 cells. Chem Biol Interact. 2014 Jul 25;218:1-9. doi: 10.1016/j.cbi.2014.04.014. Epub 2014 Apr 29.
• [15] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [16] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [17] 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.
• [18] Oxidative stress-related DNA damage and homologous recombination repairing induced by N,N-dimethylformamide. J Appl Toxicol. 2016 Jul;36(7):936-45. doi: 10.1002/jat.3226. Epub 2015 Sep 21.
• [19] DNA repair genotype interacts with arsenic exposure to increase bladder cancer risk. Toxicol Lett. 2009 May 22;187(1):10-4. doi: 10.1016/j.toxlet.2009.01.013. Epub 2009 Jan 20.