Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXTKI7Q)

• DOT Name: Adenine DNA glycosylase (MUTYH)
• Synonyms: EC 3.2.2.31; MutY homolog; hMYH
• Gene Name: MUTYH
• Related Disease:
  Familial adenomatous polyposis 2
  Colorectal cancer
  Familial ovarian cancer
  Hereditary breast carcinoma
• UniProt ID: MUTYH_HUMAN
• PDB ID: 1X51; 3N5N
• EC Number: 3.2.2.31
• Pfam ID: PF00633 ; PF00730 ; PF14815
• Sequence:
  MTPLVSRLSRLWAIMRKPRAAVGSGHRKQAASQEGRQKHAKNNSQAKPSACDGMIAECPG
  APAGLARQPEEVVLQASVSSYHLFRDVAEVTAFRGSLLSWYDQEKRDLPWRRRAEDEMDL
  DRRAYAVWVSEVMLQQTQVATVINYYTGWMQKWPTLQDLASASLEEVNQLWAGLGYYSRG
  RRLQEGARKVVEELGGHMPRTAETLQQLLPGVGRYTAGAIASIAFGQATGVVDGNVARVL
  CRVRAIGADPSSTLVSQQLWGLAQQLVDPARPGDFNQAAMELGATVCTPQRPLCSQCPVE
  SLCRARQRVEQEQLLASGSLSGSPDVEECAPNTGQCHLCLPPSEPWDQTLGVVNFPRKAS
  RKPPREESSATCVLEQPGALGAQILLVQRPNSGLLAGLWEFPSVTWEPSEQLQRKALLQE
  LQRWAGPLPATHLRHLGEVVHTFSHIKLTYQVYGLALEGQTPVTTVPPGARWLTQEEFHT
  AAVSTAMKKVFRVYQGQQPGTCMGSKRSQVSSPCSRKKPRMGQQVLDNFFRSHISTDAHS
  LNSAAQ
• Function: Involved in oxidative DNA damage repair. Initiates repair of A*oxoG to C*G by removing the inappropriately paired adenine base from the DNA backbone. Possesses both adenine and 2-OH-A DNA glycosylase activities.
• KEGG Pathway: Base excision repair (hsa03410)
• Reactome Pathway:
  Cleavage of the damaged purine (R-HSA-110331)
  Displacement of DNA glycosylase by APEX1 (R-HSA-110357)
  Defective MUTYH substrate processing (R-HSA-9608290)
  Recognition and association of DNA glycosylase with site containing an affected purine (R-HSA-110330)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Familial adenomatous polyposis 2	DIS62W3Y	Definitive	Autosomal recessive	[1]
Colorectal cancer	DISNH7P9	Disputed	Autosomal dominant	[1]
Familial ovarian cancer	DISGLR2C	Disputed	Autosomal recessive	[1]
Hereditary breast carcinoma	DISAEZT5	Disputed	Autosomal recessive	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Adenine DNA glycosylase (MUTYH) affects the activity of Arsenic trioxide.	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the methylation of Adenine DNA glycosylase (MUTYH).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Adenine DNA glycosylase (MUTYH).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Adenine DNA glycosylase (MUTYH).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Adenine DNA glycosylase (MUTYH).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Adenine DNA glycosylase (MUTYH).	[4]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Adenine DNA glycosylase (MUTYH).	[5]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Adenine DNA glycosylase (MUTYH).	[6]

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] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [3] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [4] Bortezomib induces caspase-dependent apoptosis in Hodgkin lymphoma cell lines and is associated with reduced c-FLIP expression: a gene expression profiling study with implications for potential combination therapies. Leuk Res. 2008 Feb;32(2):275-85. doi: 10.1016/j.leukres.2007.05.024. Epub 2007 Jul 19.
• [5] The use of genomics technology to investigate gene expression changes in cultured human liver cells. Toxicol In Vitro. 2001 Aug-Oct;15(4-5):399-405. doi: 10.1016/s0887-2333(01)00043-1.
• [6] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [7] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [8] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [9] 8-Oxoguanine DNA glycosylase and MutY homolog are involved in the incision of arsenite-induced DNA adducts. Toxicol Sci. 2007 Feb;95(2):376-82. doi: 10.1093/toxsci/kfl166. Epub 2006 Nov 13.