Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB09PXO)

• DOT Name: DNA repair protein complementing XP-C cells
• Synonyms: Xeroderma pigmentosum group C-complementing protein; p125
• Gene Name: XPC
• Related Disease:
  Xeroderma pigmentosum group C
  Xeroderma pigmentosum
• UniProt ID: XPC_HUMAN
• PDB ID: 2A4J; 2GGM; 2OBH; 2RVB; 8EBS; 8EBT; 8EBU; 8EBV; 8EBW; 8EBX; 8EBY
• Pfam ID: PF10403 ; PF10404 ; PF10405 ; PF03835
• Sequence:
  MARKRAAGGEPRGRELRSQKSKAKSKARREEEEEDAFEDEKPPKKSLLSKVSQGKRKRGC
  SHPGGSADGPAKKKVAKVTVKSENLKVIKDEALSDGDDLRDFPSDLKKAHHLKRGATMNE
  DSNEEEEESENDWEEVEELSEPVLGDVRESTAFSRSLLPVKPVEIEIETPEQAKTRERSE
  KIKLEFETYLRRAMKRFNKGVHEDTHKVHLLCLLANGFYRNNICSQPDLHAIGLSIIPAR
  FTRVLPRDVDTYYLSNLVKWFIGTFTVNAELSASEQDNLQTTLERRFAIYSARDDEELVH
  IFLLILRALQLLTRLVLSLQPIPLKSATAKGKKPSKERLTADPGGSSETSSQVLENHTKP
  KTSKGTKQEETFAKGTCRPSAKGKRNKGGRKKRSKPSSSEEDEGPGDKQEKATQRRPHGR
  ERRVASRVSYKEESGSDEAGSGSDFELSSGEASDPSDEDSEPGPPKQRKAPAPQRTKAGS
  KSASRTHRGSHRKDPSLPAASSSSSSSKRGKKMCSDGEKAEKRSIAGIDQWLEVFCEQEE
  KWVCVDCVHGVVGQPLTCYKYATKPMTYVVGIDSDGWVRDVTQRYDPVWMTVTRKCRVDA
  EWWAETLRPYQSPFMDREKKEDLEFQAKHMDQPLPTAIGLYKNHPLYALKRHLLKYEAIY
  PETAAILGYCRGEAVYSRDCVHTLHSRDTWLKKARVVRLGEVPYKMVKGFSNRARKARLA
  EPQLREENDLGLFGYWQTEEYQPPVAVDGKVPRNEFGNVYLFLPSMMPIGCVQLNLPNLH
  RVARKLDIDCVQAITGFDFHGGYSHPVTDGYIVCEEFKDVLLTAWENEQAVIERKEKEKK
  EKRALGNWKLLAKGLLIRERLKRRYGPKSEAAAPHTDAGGGLSSDEEEGTSSQAEAARIL
  AASWPQNREDEEKQKLKGGPKKTKREKKAAASHLFPFEQL
• Function: Involved in global genome nucleotide excision repair (GG-NER) by acting as damage sensing and DNA-binding factor component of the XPC complex. Has only a low DNA repair activity by itself which is stimulated by RAD23B and RAD23A. Has a preference to bind DNA containing a short single-stranded segment but not to damaged oligonucleotides. This feature is proposed to be related to a dynamic sensor XPC can rapidly screen duplex DNA for non-hydrogen-bonded bases by forming a transient nucleoprotein intermediate complex which matures into a stable recognition complex through an intrinsic single-stranded DNA-binding activity. The XPC complex is proposed to represent the first factor bound at the sites of DNA damage and together with other core recognition factors, XPA, RPA and the TFIIH complex, is part of the pre-incision (or initial recognition) complex. The XPC complex recognizes a wide spectrum of damaged DNA characterized by distortions of the DNA helix such as single-stranded loops, mismatched bubbles or single-stranded overhangs. The orientation of XPC complex binding appears to be crucial for inducing a productive NER. XPC complex is proposed to recognize and to interact with unpaired bases on the undamaged DNA strand which is followed by recruitment of the TFIIH complex and subsequent scanning for lesions in the opposite strand in a 5'-to-3' direction by the NER machinery. Cyclobutane pyrimidine dimers (CPDs) which are formed upon UV-induced DNA damage esacpe detection by the XPC complex due to a low degree of structural perurbation. Instead they are detected by the UV-DDB complex which in turn recruits and cooperates with the XPC complex in the respective DNA repair. In vitro, the XPC:RAD23B dimer is sufficient to initiate NER; it preferentially binds to cisplatin and UV-damaged double-stranded DNA and also binds to a variety of chemically and structurally diverse DNA adducts. XPC:RAD23B contacts DNA both 5' and 3' of a cisplatin lesion with a preference for the 5' side. XPC:RAD23B induces a bend in DNA upon binding. XPC:RAD23B stimulates the activity of DNA glycosylases TDG and SMUG1 ; In absence of DNA repair, the XPC complex also acts as a transcription coactivator: XPC interacts with the DNA-binding transcription factor E2F1 at a subset of promoters to recruit KAT2A and histone acetyltransferase complexes (HAT). KAT2A recruitment specifically promotes acetylation of histone variant H2A.Z.1/H2A.Z, but not H2A.Z.2/H2A.V, thereby promoting expression of target genes.
• KEGG Pathway: Nucleotide excision repair (hsa03420)
• Reactome Pathway:
  DNA Damage Recognition in GG-NER (R-HSA-5696394)
  Formation of Incision Complex in GG-NER (R-HSA-5696395)
  SUMOylation of DNA damage response and repair proteins (R-HSA-3108214)

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 C	DIS8DQXS	Definitive	Autosomal recessive	[1]
Xeroderma pigmentosum	DISQ9H19	Supportive	Autosomal recessive	[2]

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	DNA repair protein complementing XP-C cells affects the response to substance of Arsenic.	[23]
Arsenic trioxide	DM61TA4	Approved	DNA repair protein complementing XP-C cells affects the response to substance of Arsenic trioxide.	[24]
SCOPOLETIN	DM645FP	Investigative	DNA repair protein complementing XP-C cells affects the response to substance of SCOPOLETIN.	[25]
Kurarinone	DMH0G8W	Investigative	DNA repair protein complementing XP-C cells affects the response to substance of Kurarinone.	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of DNA repair protein complementing XP-C cells.	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of DNA repair protein complementing XP-C cells.	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of DNA repair protein complementing XP-C cells.	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of DNA repair protein complementing XP-C cells.	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of DNA repair protein complementing XP-C cells.	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of DNA repair protein complementing XP-C cells.	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of DNA repair protein complementing XP-C cells.	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of DNA repair protein complementing XP-C cells.	[10]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of DNA repair protein complementing XP-C cells.	[8]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of DNA repair protein complementing XP-C cells.	[11]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of DNA repair protein complementing XP-C cells.	[4]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide increases the expression of DNA repair protein complementing XP-C cells.	[12]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of DNA repair protein complementing XP-C cells.	[13]
Ifosfamide	DMCT3I8	Approved	Ifosfamide increases the expression of DNA repair protein complementing XP-C cells.	[4]
Colchicine	DM2POTE	Approved	Colchicine decreases the expression of DNA repair protein complementing XP-C cells.	[7]
Hydroxyurea	DMOQVU9	Approved	Hydroxyurea increases the expression of DNA repair protein complementing XP-C cells.	[14]
Adenine	DMZLHKJ	Approved	Adenine decreases the expression of DNA repair protein complementing XP-C cells.	[7]
Ximelegatran	DMU8ANS	Approved	Ximelegatran increases the expression of DNA repair protein complementing XP-C cells.	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of DNA repair protein complementing XP-C cells.	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of DNA repair protein complementing XP-C cells.	[20]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of DNA repair protein complementing XP-C cells.	[21]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of DNA repair protein complementing XP-C cells.	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of DNA repair protein complementing XP-C cells.	[17]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of DNA repair protein complementing XP-C cells.	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of DNA repair protein complementing XP-C cells.	[19]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of DNA repair protein complementing XP-C cells.	[18]

References

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• [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.
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• [10] In vitro antioxidant and antigenotoxic potentials of 3,5-O-di-galloylquinic acid extracted from Myrtus communis leaves and modulation of cell gene expression by H2O2. J Appl Toxicol. 2012 May;32(5):333-41.
• [11] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [12] Comparison of Drug Metabolism and Its Related Hepatotoxic Effects in HepaRG, Cryopreserved Human Hepatocytes, and HepG2 Cell Cultures. Biol Pharm Bull. 2018 May 1;41(5):722-732. doi: 10.1248/bpb.b17-00913. Epub 2018 Feb 14.
• [13] 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.
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• [15] 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.
• [16] The intervention mechanism of folic acid for benzo(a)pyrene toxic effects in vitro and in vivo. Eur J Cancer Prev. 2019 Jul;28(4):355-364. doi: 10.1097/CEJ.0000000000000461.
• [17] 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.
• [18] 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.
• [19] Bisphenol-A impairs cellular function and alters DNA methylation of stress pathway genes in first trimester trophoblast cells. Reprod Toxicol. 2018 Dec;82:72-79.
• [20] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [21] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [22] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [23] A distinct and replicable variant of the squamous cell carcinoma gene inositol polyphosphate-5-phosphatase modifies the susceptibility of arsenic-associated skin lesions in Bangladesh. Cancer. 2015 Jul 1;121(13):2222-9. doi: 10.1002/cncr.29291. Epub 2015 Mar 10.
• [24] XPC silencing sensitizes glioma cells to arsenic trioxide via increased oxidative damage. Toxicol Sci. 2010 Jul;116(1):183-93. doi: 10.1093/toxsci/kfq113. Epub 2010 Apr 19.
• [25] The endoperoxide ascaridol shows strong differential cytotoxicity in nucleotide excision repair-deficient cells. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):302-10. doi: 10.1016/j.taap.2012.01.006. Epub 2012 Jan 17.