Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUD091O)

• DOT Name: Twinkle mtDNA helicase
• Synonyms: EC 5.6.2.3; Progressive external ophthalmoplegia 1 protein; T7 gp4-like protein with intramitochondrial nucleoid localization; T7-like mitochondrial DNA helicase; Twinkle protein, mitochondrial
• Gene Name: TWNK
• Related Disease:
  Mitochondrial DNA depletion syndrome 7 (hepatocerebral type)
  Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3
  Autosomal dominant progressive external ophthalmoplegia
  Mitochondrial DNA depletion syndrome, hepatocerebrorenal form
  Perrault syndrome
• UniProt ID: PEO1_HUMAN
• PDB ID: 7T8B; 7T8C
• EC Number: 5.6.2.3
• Pfam ID: PF13481
• Sequence:
  MWVLLRSGYPLRILLPLRGEWMGRRGLPRNLAPGPPRRRYRKETLQALDMPVLPVTATEI
  RQYLRGHGIPFQDGHSCLRALSPFAESSQLKGQTGVTTSFSLFIDKTTGHFLCMTSLAEG
  SWEDFQASVEGRGDGAREGFLLSKAPEFEDSEEVRRIWNRAIPLWELPDQEEVQLADTMF
  GLTKVTDDTLKRFSVRYLRPARSLVFPWFSPGGSGLRGLKLLEAKCQGDGVSYEETTIPR
  PSAYHNLFGLPLISRRDAEVVLTSRELDSLALNQSTGLPTLTLPRGTTCLPPALLPYLEQ
  FRRIVFWLGDDLRSWEAAKLFARKLNPKRCFLVRPGDQQPRPLEALNGGFNLSRILRTAL
  PAWHKSIVSFRQLREEVLGELSNVEQAAGLRWSRFPDLNRILKGHRKGELTVFTGPTGSG
  KTTFISEYALDLCSQGVNTLWGSFEISNVRLARVMLTQFAEGRLEDQLDKYDHWADRFED
  LPLYFMTFHGQQSIRTVIDTMQHAVYVYDICHVIIDNLQFMMGHEQLSTDRIAAQDYIIG
  VFRKFATDNNCHVTLVIHPRKEDDDKELQTASIFGSAKASQEADNVLILQDRKLVTGPGK
  RYLQVSKNRFDGDVGVFPLEFNKNSLTFSIPPKNKARLKKIKDDTGPVAKKPSSGKKGAT
  TQNSEICSGQAPTPDQPDTSKRSK
• Function: [Isoform 1]: Mitochondrial helicase involved in mtDNA replication and repair. Might have a role in mtDNA repair. Has DNA strand separation activity needed to form a processive replication fork for leading strand synthesis which is catalyzed by the formation of a replisome complex with POLG and mtSDB. Preferentially unwinds DNA substrates with pre-existing 5'-and 3'- single-stranded tails but is also active on a 5'- flap substrate. Can dissociate the invading strand of immobile or mobile D-loop DNA structures irrespective of the single strand polarity of the third strand. In addition to its DNA strand separation activity, also has DNA strand annealing, DNA strand-exchange and DNA branch migration activities ; [Isoform 2]: Lack DNA unwinding and ATP hydrolysis activities. Does not bind single-stranded or double-stranded DNA.
• Tissue Specificity: High relative levels in skeletal muscle, testis and pancreas. Lower levels of expression in the heart, brain, placenta, lung, liver, kidney, spleen, thymus, prostate, ovary, small intestine, colon and leukocytes. Expression is coregulated with MRPL43.
• KEGG Pathway: Spinocerebellar ataxia (hsa05017)
• Reactome Pathway: Transcriptional activation of mitochondrial biogenesis (R-HSA-2151201)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial DNA depletion syndrome 7 (hepatocerebral type)	DISWVOY7	Strong	Autosomal recessive	[1]
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3	DISLLP33	Strong	Autosomal dominant	[2]
Autosomal dominant progressive external ophthalmoplegia	DISXBSXA	Supportive	Autosomal dominant	[3]
Mitochondrial DNA depletion syndrome, hepatocerebrorenal form	DISKRG1A	Supportive	Autosomal recessive	[4]
Perrault syndrome	DISG2YOV	Supportive	Autosomal recessive	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Twinkle mtDNA helicase.	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Twinkle mtDNA helicase.	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Twinkle mtDNA helicase.	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Twinkle mtDNA helicase.	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Twinkle mtDNA helicase.	[10]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Twinkle mtDNA helicase.	[8]
Melphalan	DMOLNHF	Approved	Melphalan increases the expression of Twinkle mtDNA helicase.	[11]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Twinkle mtDNA helicase.	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Twinkle mtDNA helicase.	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Twinkle mtDNA helicase.	[12]

References

• [1] Infantile onset spinocerebellar ataxia is caused by recessive mutations in mitochondrial proteins Twinkle and Twinky. Hum Mol Genet. 2005 Oct 15;14(20):2981-90. doi: 10.1093/hmg/ddi328. Epub 2005 Aug 31.
• [2] Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria. Nat Genet. 2001 Jul;28(3):223-31. doi: 10.1038/90058.
• [3] SLC25A4 and C10ORF2 Mutations in Autosomal Dominant Progressive External Ophthalmoplegia. J Clin Neurol. 2011 Mar;7(1):25-30. doi: 10.3988/jcn.2011.7.1.25. Epub 2011 Mar 31.
• [4] Exome sequencing reveals a homozygous mutation in TWINKLE as the cause of multisystemic failure including renal tubulopathy in three siblings. Mol Genet Metab. 2013 Mar;108(3):190-4. doi: 10.1016/j.ymgme.2012.12.007. Epub 2012 Dec 31.
• [5] Mutations in Twinkle primase-helicase cause Perrault syndrome with neurologic features. Neurology. 2014 Nov 25;83(22):2054-61. doi: 10.1212/WNL.0000000000001036. Epub 2014 Oct 29.
• [6] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [7] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [8] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [9] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [10] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [11] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [12] 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.
• [13] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.