Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4SXOIZ)

• DOT Name: DNA repair protein XRCC4
• Synonyms: hXRCC4; X-ray repair cross-complementing protein 4
• Gene Name: XRCC4
• Related Disease:
  Fanconi anemia complementation group Q
  Short stature, microcephaly, and endocrine dysfunction
  Obsolete microcephalic primordial dwarfism-insulin resistance syndrome
  Hereditary nonpolyposis colon cancer
• UniProt ID: XRCC4_HUMAN
• PDB ID: 1FU1; 1IK9; 3II6; 3MUD; 3Q4F; 3RWR; 3SR2; 3W03; 4XA4; 5CHX; 5CJ0; 5CJ4; 5E50; 5WJ7; 5WLZ; 6ABO; 7LSY; 7LT3; 7M3P; 7NFC; 7NFE; 8BH3; 8BHV; 8BHY; 8BOT; 8EZA; 8EZB
• Pfam ID: PF06632
• Sequence:
  MERKISRIHLVSEPSITHFLQVSWEKTLESGFVITLTDGHSAWTGTVSESEISQEADDMA
  MEKGKYVGELRKALLSGAGPADVYTFNFSKESCYFFFEKNLKDVSFRLGSFNLEKVENPA
  EVIRELICYCLDTIAENQAKNEHLQKENERLLRDWNDVQGRFEKCVSAKEALETDLYKRF
  ILVLNEKKTKIRSLHNKLLNAAQEREKDIKQEGETAICSEMTADRDPVYDESTDEESENQ
  TDLSGLASAAVSKDDSIISSLDVTDIAPSRKRRQRMQRNLGTEPKMAPQENQLQEKENSR
  PDSSLPETSKKEHISAENMSLETLRNSSPEDLFDEI
• Function: [DNA repair protein XRCC4]: DNA non-homologous end joining (NHEJ) core factor, required for double-strand break repair and V(D)J recombination. Acts as a scaffold protein that regulates recruitment of other proteins to DNA double-strand breaks (DSBs). Associates with NHEJ1/XLF to form alternating helical filaments that bridge DNA and act like a bandage, holding together the broken DNA until it is repaired. The XRCC4-NHEJ1/XLF subcomplex binds to the DNA fragments of a DSB in a highly diffusive manner and robustly bridges two independent DNA molecules, holding the broken DNA fragments in close proximity to one other. The mobility of the bridges ensures that the ends remain accessible for further processing by other repair factors. Plays a key role in the NHEJ ligation step of the broken DNA during DSB repair via direct interaction with DNA ligase IV (LIG4): the LIG4-XRCC4 subcomplex reseals the DNA breaks after the gap filling is completed. XRCC4 stabilizes LIG4, regulates its subcellular localization and enhances LIG4's joining activity. Binding of the LIG4-XRCC4 subcomplex to DNA ends is dependent on the assembly of the DNA-dependent protein kinase complex DNA-PK to these DNA ends. Promotes displacement of PNKP from processed strand break termini ; [Protein XRCC4, C-terminus]: Acts as an activator of the phospholipid scramblase activity of XKR4. This form, which is generated upon caspase-3 (CASP3) cleavage, translocates into the cytoplasm and interacts with XKR4, thereby promoting phosphatidylserine scramblase activity of XKR4 and leading to phosphatidylserine exposure on apoptotic cell surface.
• Tissue Specificity: Widely expressed.
• KEGG Pathway: Non-homologous end-joining (hsa03450)
• Reactome Pathway:
  SUMOylation of DNA damage response and repair proteins (R-HSA-3108214)
  Nonhomologous End-Joining (NHEJ) (R-HSA-5693571)
  2-LTR circle formation (R-HSA-164843)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Fanconi anemia complementation group Q	DISHYVNK	Definitive	Autosomal recessive	[1]
Short stature, microcephaly, and endocrine dysfunction	DISZI5Z5	Strong	Autosomal recessive	[2]
Obsolete microcephalic primordial dwarfism-insulin resistance syndrome	DISQPKO8	Supportive	Autosomal recessive	[1]
Hereditary nonpolyposis colon cancer	DISPA49R	Limited	Autosomal dominant	[3]

This DOT Affected the Drug Response of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	DNA repair protein XRCC4 decreases the response to substance of Cisplatin.	[26]
Mitomycin	DMH0ZJE	Approved	DNA repair protein XRCC4 decreases the response to substance of Mitomycin.	[26]
Hydroxyurea	DMOQVU9	Approved	DNA repair protein XRCC4 decreases the response to substance of Hydroxyurea.	[26]
Floxuridine	DM04LR2	Approved	DNA repair protein XRCC4 decreases the response to substance of Floxuridine.	[26]
Aphidicolin	DM71C6D	Discontinued in Phase 1	DNA repair protein XRCC4 decreases the response to substance of Aphidicolin.	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of DNA repair protein XRCC4.	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of DNA repair protein XRCC4.	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of DNA repair protein XRCC4.	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of DNA repair protein XRCC4.	[7]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of DNA repair protein XRCC4.	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of DNA repair protein XRCC4.	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of DNA repair protein XRCC4.	[10]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of DNA repair protein XRCC4.	[11]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of DNA repair protein XRCC4.	[12]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of DNA repair protein XRCC4.	[13]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of DNA repair protein XRCC4.	[10]
Chlorpromazine	DMBGZI3	Phase 3 Trial	Chlorpromazine decreases the expression of DNA repair protein XRCC4.	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of DNA repair protein XRCC4.	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of DNA repair protein XRCC4.	[17]
Taxifolin	DMQJSF9	Preclinical	Taxifolin increases the expression of DNA repair protein XRCC4.	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of DNA repair protein XRCC4.	[21]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of DNA repair protein XRCC4.	[22]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of DNA repair protein XRCC4.	[23]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of DNA repair protein XRCC4.	[24]
Taurine	DMVW7N3	Investigative	Taurine increases the expression of DNA repair protein XRCC4.	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Camptothecin	DM6CHNJ	Phase 3	Camptothecin increases the methylation of DNA repair protein XRCC4.	[14]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of DNA repair protein XRCC4.	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of DNA repair protein XRCC4.	[19]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of DNA repair protein XRCC4.	[19]

References

• [1] Mutations in the NHEJ component XRCC4 cause primordial dwarfism. Am J Hum Genet. 2015 Mar 5;96(3):412-24. doi: 10.1016/j.ajhg.2015.01.013. Epub 2015 Feb 26.
• [2] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [3] 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.
• [4] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [7] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [8] Curcumin prevents DNA damage and enhances the repair potential in a chronically arsenic-exposed human population in West Bengal, India. Eur J Cancer Prev. 2011 Mar;20(2):123-31. doi: 10.1097/cej.0b013e328341017a.
• [9] 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.
• [10] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [11] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [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] In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells. Mol Cancer Ther. 2005 Jun;4(6):885-900.
• [14] Reduced camptothecin sensitivity of estrogen receptor-positive human breast cancer cells following exposure to di(2-ethylhexyl)phthalate (DEHP) is associated with DNA methylation changes. Environ Toxicol. 2019 Apr;34(4):401-414.
• [15] Effects of chlorpromazine with and without UV irradiation on gene expression of HepG2 cells. Mutat Res. 2005 Aug 4;575(1-2):47-60. doi: 10.1016/j.mrfmmm.2005.03.002. Epub 2005 Apr 26.
• [16] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [17] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [18] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [19] 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.
• [20] The chemopreventive effect of taxifolin is exerted through ARE-dependent gene regulation. Biol Pharm Bull. 2007 Jun;30(6):1074-9.
• [21] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [23] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [24] Nickel induces transcriptional down-regulation of DNA repair pathways in tumorigenic and non-tumorigenic lung cells. Carcinogenesis. 2017 Jun 1;38(6):627-637.
• [25] 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.
• [26] Differences in sensitivity to DNA-damaging Agents between XRCC4- and Artemis-deficient human cells. J Radiat Res. 2011;52(4):415-24. doi: 10.1269/jrr.10168.