Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJB2PV4)

• DOT Name: DNA repair protein XRCC2
• Synonyms: X-ray repair cross-complementing protein 2
• Gene Name: XRCC2
• Related Disease:
  Fanconi anemia complementation group U
  Fanconi's anemia
  Obsolete male infertility with azoospermia or oligozoospermia due to single gene mutation
  Breast cancer
  Premature ovarian failure 17
  Spermatogenic failures 50
  Hereditary breast carcinoma
  Familial ovarian cancer
• UniProt ID: XRCC2_HUMAN
• PDB ID: 8FAZ; 8GBJ; 8OUY; 8OUZ
• Pfam ID: PF08423
• Sequence:
  MCSAFHRAESGTELLARLEGRSSLKEIEPNLFADEDSPVHGDILEFHGPEGTGKTEMLYH
  LTARCILPKSEGGLEVEVLFIDTDYHFDMLRLVTILEHRLSQSSEEIIKYCLGRFFLVYC
  SSSTHLLLTLYSLESMFCSHPSLCLLILDSLSAFYWIDRVNGGESVNLQESTLRKCSQCL
  EKLVNDYRLVLFATTQTIMQKASSSSEEPSHASRRLCDVDIDYRPYLCKAWQQLVKHRMF
  FSKQDDSQSSNQFSLVSRCLKSNSLKKHFFIIGESGVEFC
• 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 BCDX2 which acts in the BRCA1-BRCA2-dependent HR pathway. Upon DNA damage, BCDX2 acts downstream of BRCA2 recruitment and upstream of RAD51 recruitment. BCDX2 binds predominantly to the intersection of the four duplex arms of the Holliday junction and to junction of replication forks. The BCDX2 complex was originally reported to bind single-stranded DNA, single-stranded gaps in duplex DNA and specifically to nicks in duplex DNA.
• 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)
  Presynaptic phase of homologous DNA pairing and strand exchange (R-HSA-5693616)
  Defective homologous recombination repair (HRR) due to BRCA1 loss of function (R-HSA-9701192)
  Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function (R-HSA-9704331)
  Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function (R-HSA-9704646)
  Impaired BRCA2 binding to PALB2 (R-HSA-9709603)
  HDR through Homologous Recombination (HRR) (R-HSA-5685942)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Fanconi anemia complementation group U	DISSOVEA	Moderate	Autosomal recessive	[1]
Fanconi's anemia	DISGW6Q8	Supportive	Autosomal recessive	[2]
Obsolete male infertility with azoospermia or oligozoospermia due to single gene mutation	DIS56JR8	Supportive	Autosomal dominant	[3]
Breast cancer	DIS7DPX1	Disputed	Autosomal dominant	[1]
Premature ovarian failure 17	DISEPD0O	Limited	Unknown	[4]
Spermatogenic failures 50	DIS7WO2Y	Limited	Unknown	[3]
Hereditary breast carcinoma	DISAEZT5	Refuted	Autosomal dominant	[5]
Familial ovarian cancer	DISGLR2C	No Known	Autosomal dominant	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DNA repair protein XRCC2.	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of DNA repair protein XRCC2.	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of DNA repair protein XRCC2.	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of DNA repair protein XRCC2.	[9]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of DNA repair protein XRCC2.	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of DNA repair protein XRCC2.	[11]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of DNA repair protein XRCC2.	[11]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of DNA repair protein XRCC2.	[12]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of DNA repair protein XRCC2.	[13]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of DNA repair protein XRCC2.	[14]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of DNA repair protein XRCC2.	[15]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of DNA repair protein XRCC2.	[16]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of DNA repair protein XRCC2.	[17]
Lucanthone	DMZLBUO	Approved	Lucanthone decreases the expression of DNA repair protein XRCC2.	[18]
Dihydroxyacetone	DMM1LG2	Approved	Dihydroxyacetone increases the expression of DNA repair protein XRCC2.	[19]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of DNA repair protein XRCC2.	[20]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of DNA repair protein XRCC2.	[21]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of DNA repair protein XRCC2.	[22]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of DNA repair protein XRCC2.	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of DNA repair protein XRCC2.	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of DNA repair protein XRCC2.	[26]
Fenthion	DMKEG49	Investigative	Fenthion decreases the expression of DNA repair protein XRCC2.	[28]
Dimethylformamide	DML6O4N	Investigative	Dimethylformamide increases the expression of DNA repair protein XRCC2.	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of DNA repair protein XRCC2.	[24]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of DNA repair protein XRCC2.	[27]

References

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• [3] XRCC2 mutation causes meiotic arrest, azoospermia and infertility. J Med Genet. 2018 Sep;55(9):628-636. doi: 10.1136/jmedgenet-2017-105145. Epub 2018 Jul 24.
• [4] XRCC2 mutation causes premature ovarian insufficiency as well as non-obstructive azoospermia in humans. Clin Genet. 2019 Mar;95(3):442-443. doi: 10.1111/cge.13475. Epub 2018 Nov 29.
• [5] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
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• [12] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [13] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [14] Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
• [15] Increased sensitivity for troglitazone-induced cytotoxicity using a human in vitro co-culture model. Toxicol In Vitro. 2009 Oct;23(7):1387-95.
• [16] 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.
• [17] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [18] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [19] The sunless tanning agent dihydroxyacetone induces stress response gene expression and signaling in cultured human keratinocytes and reconstructed epidermis. Redox Biol. 2020 Sep;36:101594. doi: 10.1016/j.redox.2020.101594. Epub 2020 May 29.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [22] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [23] 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.
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• [26] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [27] 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.
• [28] The cytotoxicity and genotoxicity of single and combined fenthion and terbufos treatments in human liver cells and zebrafish embryos. Sci Total Environ. 2021 Mar 1;758:143597. doi: 10.1016/j.scitotenv.2020.143597. Epub 2020 Nov 10.
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