Details of Drug Off-Target (DOT)

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

• DOT Name: X-ray repair cross-complementing protein 6
• Synonyms: EC 3.6.4.-; EC 4.2.99.-; 5'-deoxyribose-5-phosphate lyase Ku70; 5'-dRP lyase Ku70; 70 kDa subunit of Ku antigen; ATP-dependent DNA helicase 2 subunit 1; ATP-dependent DNA helicase II 70 kDa subunit; CTC box-binding factor 75 kDa subunit; CTC75; CTCBF; DNA repair protein XRCC6; Lupus Ku autoantigen protein p70; Ku70; Thyroid-lupus autoantigen; TLAA; X-ray repair complementing defective repair in Chinese hamster cells 6
• Gene Name: XRCC6
• Related Disease: Autism spectrum disorder
• UniProt ID: XRCC6_HUMAN
• PDB ID: 1JEQ ; 1JEY ; 1JJR ; 3RZX ; 5Y3R ; 6ERF ; 6ERG ; 6ERH ; 6ZHA ; 6ZHE ; 7AXZ ; 7K0Y ; 7K1J ; 7K1K ; 7K1N ; 7LSY ; 7LT3 ; 7NFC ; 7NFE ; 7SGL ; 7SU3 ; 7Z6O ; 7Z87 ; 7Z88 ; 7ZT6 ; 7ZVT ; 7ZWA ; 7ZYG ; 8AG4 ; 8AG5 ; 8ASC ; 8BH3 ; 8BHV ; 8BHY ; 8BOT ; 8EZA ; 8EZB
• EC Number: 3.6.4.-; 4.2.99.-
• Pfam ID: PF02735 ; PF03730 ; PF03731 ; PF02037
• Sequence:
  MSGWESYYKTEGDEEAEEEQEENLEASGDYKYSGRDSLIFLVDASKAMFESQSEDELTPF
  DMSIQCIQSVYISKIISSDRDLLAVVFYGTEKDKNSVNFKNIYVLQELDNPGAKRILELD
  QFKGQQGQKRFQDMMGHGSDYSLSEVLWVCANLFSDVQFKMSHKRIMLFTNEDNPHGNDS
  AKASRARTKAGDLRDTGIFLDLMHLKKPGGFDISLFYRDIISIAEDEDLRVHFEESSKLE
  DLLRKVRAKETRKRALSRLKLKLNKDIVISVGIYNLVQKALKPPPIKLYRETNEPVKTKT
  RTFNTSTGGLLLPSDTKRSQIYGSRQIILEKEETEELKRFDDPGLMLMGFKPLVLLKKHH
  YLRPSLFVYPEESLVIGSSTLFSALLIKCLEKEVAALCRYTPRRNIPPYFVALVPQEEEL
  DDQKIQVTPPGFQLVFLPFADDKRKMPFTEKIMATPEQVGKMKAIVEKLRFTYRSDSFEN
  PVLQQHFRNLEALALDLMEPEQAVDLTLPKVEAMNKRLGSLVDEFKELVYPPDYNPEGKV
  TKRKHDNEGSGSKRPKVEYSEEELKTHISKGTLGKFTVPMLKEACRAYGLKSGLKKQELL
  EALTKHFQD
• Function: Single-stranded DNA-dependent ATP-dependent helicase that plays a key role in DNA non-homologous end joining (NHEJ) by recruiting DNA-PK to DNA. Required for double-strand break repair and V(D)J recombination. Also has a role in chromosome translocation. Has a role in chromosome translocation. The DNA helicase II complex binds preferentially to fork-like ends of double-stranded DNA in a cell cycle-dependent manner. It works in the 3'-5' direction. During NHEJ, the XRCC5-XRRC6 dimer performs the recognition step: it recognizes and binds to the broken ends of the DNA and protects them from further resection. Binding to DNA may be mediated by XRCC6. The XRCC5-XRRC6 dimer acts as a regulatory subunit of the DNA-dependent protein kinase complex DNA-PK by increasing the affinity of the catalytic subunit PRKDC to DNA by 100-fold. The XRCC5-XRRC6 dimer is probably involved in stabilizing broken DNA ends and bringing them together. The assembly of the DNA-PK complex to DNA ends is required for the NHEJ ligation step. Probably also acts as a 5'-deoxyribose-5-phosphate lyase (5'-dRP lyase), by catalyzing the beta-elimination of the 5' deoxyribose-5-phosphate at an abasic site near double-strand breaks. 5'-dRP lyase activity allows to 'clean' the termini of abasic sites, a class of nucleotide damage commonly associated with strand breaks, before such broken ends can be joined. The XRCC5-XRRC6 dimer together with APEX1 acts as a negative regulator of transcription. In association with NAA15, the XRCC5-XRRC6 dimer binds to the osteocalcin promoter and activates osteocalcin expression. Plays a role in the regulation of DNA virus-mediated innate immune response by assembling into the HDP-RNP complex, a complex that serves as a platform for IRF3 phosphorylation and subsequent innate immune response activation through the cGAS-STING pathway.
• KEGG Pathway: Non-homologous end-joining (hsa03450)
• Reactome Pathway:
  Cytosolic sensors of pathogen-associated DNA (R-HSA-1834949)
  IRF3-mediated induction of type I IFN (R-HSA-3270619)
  Nonhomologous End-Joining (NHEJ) (R-HSA-5693571)
  Neutrophil degranulation (R-HSA-6798695)
  2-LTR circle formation (R-HSA-164843)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism spectrum disorder	DISXK8NV	Limited	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of X-ray repair cross-complementing protein 6.	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of X-ray repair cross-complementing protein 6.	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of X-ray repair cross-complementing protein 6.	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of X-ray repair cross-complementing protein 6.	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of X-ray repair cross-complementing protein 6.	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of X-ray repair cross-complementing protein 6.	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of X-ray repair cross-complementing protein 6.	[8]
Fludarabine	DMVRLT7	Approved	Fludarabine decreases the activity of X-ray repair cross-complementing protein 6.	[10]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of X-ray repair cross-complementing protein 6.	[11]
NVP-LAQ824	DM8JWNA	Phase 3	NVP-LAQ824 decreases the activity of X-ray repair cross-complementing protein 6.	[10]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of X-ray repair cross-complementing protein 6.	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of X-ray repair cross-complementing protein 6.	[14]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of X-ray repair cross-complementing protein 6.	[16]
Fenthion	DMKEG49	Investigative	Fenthion increases the expression of X-ray repair cross-complementing protein 6.	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Decitabine	DMQL8XJ	Approved	Decitabine affects the methylation of X-ray repair cross-complementing protein 6.	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of X-ray repair cross-complementing protein 6.	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the acetylation of X-ray repair cross-complementing protein 6.	[15]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of X-ray repair cross-complementing protein 6.	[13]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] 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.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] Identification of estrogen-induced genes downregulated by AhR agonists in MCF-7 breast cancer cells using suppression subtractive hybridization. Gene. 2001 Jan 10;262(1-2):207-14. doi: 10.1016/s0378-1119(00)00530-8.
• [5] 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.
• [6] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [7] 1,25-Dihydroxyvitamin D3 suppresses gene expression of eukaryotic translation initiation factor 2 in human promyelocytic leukemia HL-60 cells. Cell Struct Funct. 2005;30(1):1-6. doi: 10.1247/csf.30.1.
• [8] Vorinostat, a histone deacetylase inhibitor, enhances the response of human tumor cells to ionizing radiation through prolongation of gamma-H2AX foci. Mol Cancer Ther. 2006 Aug;5(8):1967-74. doi: 10.1158/1535-7163.MCT-06-0022.
• [9] Ornithine decarboxylase antizyme upregulates DNA-dependent protein kinase and enhances the nonhomologous end-joining repair of DNA double-strand breaks in human oral cancer cells. Biochemistry. 2007 Aug 7;46(31):8920-32. doi: 10.1021/bi7000328. Epub 2007 Jul 14.
• [10] Role of histone deacetylase inhibitor-induced reactive oxygen species and DNA damage in LAQ-824/fludarabine antileukemic interactions. Mol Cancer Ther. 2008 Oct;7(10):3285-97. doi: 10.1158/1535-7163.MCT-08-0385.
• [11] Curcumin suppresses growth and chemoresistance of human glioblastoma cells via AP-1 and NFkappaB transcription factors. J Neurochem. 2007 Jul;102(2):522-38. doi: 10.1111/j.1471-4159.2007.04633.x.
• [12] 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.
• [13] 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.
• [14] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [15] Histone deacetylase inhibitors decrease NHEJ both by acetylation of repair factors and trapping of PARP1 at DNA double-strand breaks in chromatin. Leuk Res. 2016 Jun;45:14-23. doi: 10.1016/j.leukres.2016.03.007. Epub 2016 Mar 30.
• [16] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [17] 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.