Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6V9IDI)

• DOT Name: Abscission/NoCut checkpoint regulator
• Synonyms: ANCHR; MLL partner containing FYVE domain; Zinc finger FYVE domain-containing protein 19
• Gene Name: ZFYVE19
• Related Disease: Cholestasis, progressive familial intrahepatic, 9
• UniProt ID: ANCHR_HUMAN
• Pfam ID: PF01363
• Sequence:
  MNYDSQQPPLPPLPYAGCRRASGFPALGRGGTVPVGVWGGAGQGREGRSWGEGPRGPGLG
  RRDLSSADPAVLGATMESRCYGCAVKFTLFKKEYGCKNCGRAFCSGCLSFSAAVPRTGNT
  QQKVCKQCHEVLTRGSSANASKWSPPQNYKKRVAALEAKQKPSTSQSQGLTRQDQMIAER
  LARLRQENKPKLVPSQAEIEARLAALKDERQGSIPSTQEMEARLAALQGRVLPSQTPQPA
  HHTPDTRTQAQQTQDLLTQLAAEVAIDESWKGGGPAASLQNDLNQGGPGSTNSKRQANWS
  LEEEKSRLLAEAALELREENTRQERILALAKRLAMLRGQDPERVTLQDYRLPDSDDDEDE
  ETAIQRVLQQLTEEASLDEASGFNIPAEQASRPWTQPRGAEPEAQDVDPRPEAEEEELPW
  CCICNEDATLRCAGCDGDLFCARCFREGHDAFELKEHQTSAYSPPRAGQEH
• Function: Key regulator of abscission step in cytokinesis: part of the cytokinesis checkpoint, a process required to delay abscission to prevent both premature resolution of intercellular chromosome bridges and accumulation of DNA damage. Together with CHMP4C, required to retain abscission-competent VPS4 (VPS4A and/or VPS4B) at the midbody ring until abscission checkpoint signaling is terminated at late cytokinesis. Deactivation of AURKB results in dephosphorylation of CHMP4C followed by its dissociation from ZFYVE19/ANCHR and VPS4 and subsequent abscission.
• Tissue Specificity: Detected in brain, heart, skeletal muscle and kidney . Expressed in the liver (at protein level) .

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cholestasis, progressive familial intrahepatic, 9	DISR5S7G	Strong	Autosomal recessive	[1]

9 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 Abscission/NoCut checkpoint regulator.	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Abscission/NoCut checkpoint regulator.	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Abscission/NoCut checkpoint regulator.	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Abscission/NoCut checkpoint regulator.	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Abscission/NoCut checkpoint regulator.	[6]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Abscission/NoCut checkpoint regulator.	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Abscission/NoCut checkpoint regulator.	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Abscission/NoCut checkpoint regulator.	[9]
Paraoxon	DMN4ZKC	Investigative	Paraoxon increases the expression of Abscission/NoCut checkpoint regulator.	[12]

2 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 Abscission/NoCut checkpoint regulator.	[10]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the phosphorylation of Abscission/NoCut checkpoint regulator.	[11]

References

• [1] Biallelic loss-of-function ZFYVE19 mutations are associated with congenital hepatic fibrosis, sclerosing cholangiopathy and high-GGT cholestasis. J Med Genet. 2021 Aug;58(8):514-525. doi: 10.1136/jmedgenet-2019-106706. Epub 2020 Jul 31.
• [2] 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.
• [3] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [6] 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.
• [7] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.
• [12] Paraoxon-induced protein expression changes to SH-SY5Y cells. Chem Res Toxicol. 2010 Nov 15;23(11):1656-62. doi: 10.1021/tx100192f. Epub 2010 Oct 8.