Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC5LPXX)

• DOT Name: Mitochondrial genome maintenance exonuclease 1 (MGME1)
• Synonyms: EC 3.1.-.-
• Gene Name: MGME1
• Related Disease:
  Mitochondrial disease
  Hutchinson-Gilford progeria syndrome
  Microcephaly
  Mitochondrial DNA depletion syndrome 11
  Osteoporosis
  Respiratory failure
• UniProt ID: MGME1_HUMAN
• PDB ID: 5ZYT; 5ZYU; 5ZYV; 5ZYW
• EC Number: 3.1.-.-
• Pfam ID: PF12705
• Sequence:
  MKMKLFQTICRQLRSSKFSVESAALVAFSTSSYSCGRKKKVNPYEEVDQEKYSNLVQSVL
  SSRGVAQTPGSVEEDALLCGPVSKHKLPNQGEDRRVPQNWFPIFNPERSDKPNASDPSVP
  LKIPLQRNVIPSVTRVLQQTMTKQQVFLLERWKQRMILELGEDGFKEYTSNVFLQGKRFH
  EALESILSPQETLKERDENLLKSGYIESVQHILKDVSGVRALESAVQHETLNYIGLLDCV
  AEYQGKLCVIDWKTSEKPKPFIQSTFDNPLQVVAYMGAMNHDTNYSFQVQCGLIVVAYKD
  GSPAHPHFMDAELCSQYWTKWLLRLEEYTEKKKNQNIQKPEYSE
• Function: Metal-dependent single-stranded DNA (ssDNA) exonuclease involved in mitochondrial genome maintenance. Has preference for 5'-3' exonuclease activity but is also capable of endoduclease activity on linear substrates. Necessary for maintenance of proper 7S DNA levels. Probably involved in mitochondrial DNA (mtDNA) repair, possibly via the processing of displaced DNA containing Okazaki fragments during RNA-primed DNA synthesis on the lagging strand or via processing of DNA flaps during long-patch base excision repair. Specifically binds 5-hydroxymethylcytosine (5hmC)-containing DNA in stem cells.

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial disease	DISKAHA3	Definitive	Autosomal recessive	[1]
Hutchinson-Gilford progeria syndrome	DISY55BU	Strong	Biomarker	[2]
Microcephaly	DIS2GRD8	Strong	CausalMutation	[3]
Mitochondrial DNA depletion syndrome 11	DISGJJ69	Strong	Autosomal recessive	[4]
Osteoporosis	DISF2JE0	Strong	Biomarker	[5]
Respiratory failure	DISVMYJO	Strong	Genetic Variation	[6]

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 Mitochondrial genome maintenance exonuclease 1 (MGME1).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Mitochondrial genome maintenance exonuclease 1 (MGME1).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Mitochondrial genome maintenance exonuclease 1 (MGME1).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Mitochondrial genome maintenance exonuclease 1 (MGME1).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Mitochondrial genome maintenance exonuclease 1 (MGME1).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Mitochondrial genome maintenance exonuclease 1 (MGME1).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Mitochondrial genome maintenance exonuclease 1 (MGME1).	[13]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Mitochondrial genome maintenance exonuclease 1 (MGME1).	[13]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Mitochondrial genome maintenance exonuclease 1 (MGME1).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Mitochondrial genome maintenance exonuclease 1 (MGME1).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Mitochondrial genome maintenance exonuclease 1 (MGME1).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Mitochondrial genome maintenance exonuclease 1 (MGME1).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Mitochondrial genome maintenance exonuclease 1 (MGME1).	[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] Mice lacking the mitochondrial exonuclease MGME1 accumulate mtDNA deletions without developing progeria.Nat Commun. 2018 Mar 23;9(1):1202. doi: 10.1038/s41467-018-03552-x.
• [3] Homozygous c.359del variant in MGME1 is associated with early onset cerebellar ataxia.Eur J Med Genet. 2017 Oct;60(10):533-535. doi: 10.1016/j.ejmg.2017.07.010. Epub 2017 Jul 12.
• [4] Loss-of-function mutations in MGME1 impair mtDNA replication and cause multisystemic mitochondrial disease. Nat Genet. 2013 Feb;45(2):214-9. doi: 10.1038/ng.2501. Epub 2013 Jan 13.
• [5] MiR-203 is involved in osteoporosis by regulating DKK1 and inhibiting osteogenic differentiation of MSCs.Eur Rev Med Pharmacol Sci. 2018 Aug;22(16):5098-5105. doi: 10.26355/eurrev_201808_15703.
• [6] Structural insights into DNA degradation by human mitochondrial nuclease MGME1.Nucleic Acids Res. 2018 Nov 16;46(20):11075-11088. doi: 10.1093/nar/gky855.
• [7] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [8] 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.
• [9] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [12] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [13] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [14] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [15] 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.
• [16] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [17] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.