Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO2MEFR)

• DOT Name: DNA repair protein complementing XP-A cells
• Synonyms: Xeroderma pigmentosum group A-complementing protein
• Gene Name: XPA
• Related Disease:
  Xeroderma pigmentosum group A
  Xeroderma pigmentosum
• UniProt ID: XPA_HUMAN
• PDB ID: 1D4U; 1XPA; 2JNW; 6J44; 6LAE; 6RO4; 7AD8; 8EBT; 8EBU; 8EBX; 8EBY
• Pfam ID: PF05181 ; PF01286
• Sequence:
  MAAADGALPEAAALEQPAELPASVRASIERKRQRALMLRQARLAARPYSATAAAATGGMA
  NVKAAPKIIDTGGGFILEEEEEEEQKIGKVVHQPGPVMEFDYVICEECGKEFMDSYLMNH
  FDLPTCDNCRDADDKHKLITKTEAKQEYLLKDCDLEKREPPLKFIVKKNPHHSQWGDMKL
  YLKLQIVKRSLEVWGSQEALEEAKEVRQENREKMKQKKFDKKVKELRRAVRSSVWKRETI
  VHQHEYGPEENLEDDMYRKTCTMCGHELTYEKM
• Function: Involved in DNA excision repair. Initiates repair by binding to damaged sites with various affinities, depending on the photoproduct and the transcriptional state of the region. Required for UV-induced CHEK1 phosphorylation and the recruitment of CEP164 to cyclobutane pyrimidine dimmers (CPD), sites of DNA damage after UV irradiation.
• Tissue Specificity: Expressed in various cell lines and in skin fibroblasts.
• KEGG Pathway:
  Platinum drug resistance (hsa01524)
  Nucleotide excision repair (hsa03420)
• Reactome Pathway:
  Dual Incision in GG-NER (R-HSA-5696400)
  Formation of TC-NER Pre-Incision Complex (R-HSA-6781823)
  Dual incision in TC-NER (R-HSA-6782135)
  Formation of Incision Complex in GG-NER (R-HSA-5696395)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Xeroderma pigmentosum group A	DIS38HWC	Definitive	Autosomal recessive	[1]
Xeroderma pigmentosum	DISQ9H19	Supportive	Autosomal recessive	[2]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	DNA repair protein complementing XP-A cells decreases the response to substance of Cisplatin.	[16]
Arsenic	DMTL2Y1	Approved	DNA repair protein complementing XP-A cells affects the response to substance of Arsenic.	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of DNA repair protein complementing XP-A cells.	[3]

12 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 complementing XP-A cells.	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DNA repair protein complementing XP-A cells.	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of DNA repair protein complementing XP-A cells.	[6]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of DNA repair protein complementing XP-A cells.	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of DNA repair protein complementing XP-A cells.	[8]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of DNA repair protein complementing XP-A cells.	[9]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of DNA repair protein complementing XP-A cells.	[10]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of DNA repair protein complementing XP-A cells.	[11]
Ximelegatran	DMU8ANS	Approved	Ximelegatran increases the expression of DNA repair protein complementing XP-A cells.	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of DNA repair protein complementing XP-A cells.	[13]
Taxifolin	DMQJSF9	Preclinical	Taxifolin increases the expression of DNA repair protein complementing XP-A cells.	[14]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of DNA repair protein complementing XP-A cells.	[15]

References

• [1] 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.
• [2] Xeroderma Pigmentosum. 2003 Jun 20 [updated 2022 Mar 24]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [3] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [8] 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.
• [9] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [10] Combination of oxaliplatin and irinotecan on human colon cancer cell lines: activity in vitro and in vivo. Anticancer Drugs. 2001 Oct;12(9):741-51. doi: 10.1097/00001813-200110000-00006.
• [11] XPC is essential for nucleotide excision repair of zidovudine-induced DNA damage in human hepatoma cells. Toxicol Appl Pharmacol. 2011 Mar 1;251(2):155-62. doi: 10.1016/j.taap.2010.12.009. Epub 2010 Dec 28.
• [12] Pharmacological inhibition of Rho-kinase (ROCK) signaling enhances cisplatin resistance in neuroblastoma cells. Int J Oncol. 2010 Nov;37(5):1297-305. doi: 10.3892/ijo_00000781.
• [13] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [14] The chemopreventive effect of taxifolin is exerted through ARE-dependent gene regulation. Biol Pharm Bull. 2007 Jun;30(6):1074-9.
• [15] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [16] ABCC5, ERCC2, XPA and XRCC1 transcript abundance levels correlate with cisplatin chemoresistance in non-small cell lung cancer cell lines. Mol Cancer. 2005 May 9;4(1):18. doi: 10.1186/1476-4598-4-18.
• [17] Polymorphisms in nucleotide excision repair genes, arsenic exposure, and non-melanoma skin cancer in New Hampshire. Environ Health Perspect. 2007 Aug;115(8):1231-6. doi: 10.1289/ehp.10096.