Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVZ4E60)

• DOT Name: Crossover junction endonuclease MUS81 (MUS81)
• Synonyms: EC 3.1.22.-
• Gene Name: MUS81
• Related Disease:
  Non-small-cell lung cancer
  Advanced cancer
  Arterial tortuosity syndrome
  Bloom syndrome
  Breast cancer
  Breast carcinoma
  Carcinoma
  Colon cancer
  Colon carcinoma
  Epithelial ovarian cancer
  Esophageal adenocarcinoma
  Exocrine pancreatic insufficiency
  Familial multiple trichoepithelioma
  Hepatocellular carcinoma
  Marfan syndrome
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Xeroderma pigmentosum group F
  Chromosomal disorder
  Gastric cancer
  Stomach cancer
• UniProt ID: MUS81_HUMAN
• PDB ID: 2MC3; 2ZIX; 4P0P; 4P0Q; 4P0R; 4P0S; 6VWB; 7BU5; 7F6L
• EC Number: 3.1.22.-
• Pfam ID: PF21292 ; PF02732 ; PF21136
• Sequence:
  MAAPVRLGRKRPLPACPNPLFVRWLTEWRDEATRSRRRTRFVFQKALRSLRRYPLPLRSG
  KEAKILQHFGDGLCRMLDERLQRHRTSGGDHAPDSPSGENSPAPQGRLAEVQDSSMPVPA
  QPKAGGSGSYWPARHSGARVILLVLYREHLNPNGHHFLTKEELLQRCAQKSPRVAPGSAR
  PWPALRSLLHRNLVLRTHQPARYSLTPEGLELAQKLAESEGLSLLNVGIGPKEPPGEETA
  VPGAASAELASEAGVQQQPLELRPGEYRVLLCVDIGETRGGGHRPELLRELQRLHVTHTV
  RKLHVGDFVWVAQETNPRDPANPGELVLDHIVERKRLDDLCSSIIDGRFREQKFRLKRCG
  LERRVYLVEEHGSVHNLSLPESTLLQAVTNTQVIDGFFVKRTADIKESAAYLALLTRGLQ
  RLYQGHTLRSRPWGTPGNPESGAMTSPNPLCSLLTFSDFNAGAIKNKAQSVREVFARQLM
  QVRGVSGEKAAALVDRYSTPASLLAAYDACATPKEQETLLSTIKCGRLQRNLGPALSRTL
  SQLYCSYGPLT
• Function: Interacts with EME1 and EME2 to form a DNA structure-specific endonuclease with substrate preference for branched DNA structures with a 5'-end at the branch nick. Typical substrates include 3'-flap structures, replication forks and nicked Holliday junctions. Plays an essential role in mitosis for the processing of stalled or collapsed replication forks.
• Tissue Specificity: Widely expressed.
• KEGG Pathway:
  Homologous recombi.tion (hsa03440)
  Fanconi anemia pathway (hsa03460)
• Reactome Pathway:
  Fanconi Anemia Pathway (R-HSA-6783310)
  Resolution of D-loop Structures through Holliday Junction Intermediates (R-HSA-5693568)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-small-cell lung cancer	DIS5Y6R9	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Posttranslational Modification	[2]
Arterial tortuosity syndrome	DISWG36B	Strong	Biomarker	[3]
Bloom syndrome	DISKXQ7J	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[5]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[5]
Carcinoma	DISH9F1N	Strong	Altered Expression	[6]
Colon cancer	DISVC52G	Strong	Biomarker	[7]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[7]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[8]
Esophageal adenocarcinoma	DISODWFP	Strong	Biomarker	[9]
Exocrine pancreatic insufficiency	DISCZYU2	Strong	Biomarker	[10]
Familial multiple trichoepithelioma	DISKZAUY	Strong	Biomarker	[9]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[7]
Marfan syndrome	DISVEUWZ	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[11]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[12]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[12]
Xeroderma pigmentosum group F	DISRKRYY	Strong	Biomarker	[12]
Chromosomal disorder	DISM5BB5	Limited	Biomarker	[13]
Gastric cancer	DISXGOUK	Limited	Biomarker	[14]
Stomach cancer	DISKIJSX	Limited	Biomarker	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Crossover junction endonuclease MUS81 (MUS81).	[15]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the sumoylation of Crossover junction endonuclease MUS81 (MUS81).	[18]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Crossover junction endonuclease MUS81 (MUS81).	[20]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Crossover junction endonuclease MUS81 (MUS81).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Crossover junction endonuclease MUS81 (MUS81).	[23]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Crossover junction endonuclease MUS81 (MUS81).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Crossover junction endonuclease MUS81 (MUS81).	[16]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Crossover junction endonuclease MUS81 (MUS81).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Crossover junction endonuclease MUS81 (MUS81).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Crossover junction endonuclease MUS81 (MUS81).	[21]

References

• [1] Increased expression and activity of repair genes TDP1 and XPF in non-small cell lung cancer.Lung Cancer. 2007 Mar;55(3):303-11. doi: 10.1016/j.lungcan.2006.10.019. Epub 2006 Nov 21.
• [2] DNA REPAIR. Mus81 and converging forks limit the mutagenicity of replication fork breakage.Science. 2015 Aug 14;349(6249):742-7. doi: 10.1126/science.aaa8391.
• [3] Perturbations of vascular homeostasis and aortic valve abnormalities in fibulin-4 deficient mice.Circ Res. 2007 Mar 16;100(5):738-46. doi: 10.1161/01.RES.0000260181.19449.95. Epub 2007 Feb 9.
• [4] Aberrant chromosome morphology in human cells defective for Holliday junction resolution.Nature. 2011 Mar 31;471(7340):642-6. doi: 10.1038/nature09790. Epub 2011 Mar 13.
• [5] Genetic variation in genes interacting with BRCA1/2 and risk of breast cancer in the Cypriot population.Breast Cancer Res Treat. 2010 May;121(1):147-56. doi: 10.1007/s10549-009-0518-7. Epub 2009 Aug 28.
• [6] Down-regulation of Mus81 as a potential marker for the malignancy of gastric cancer.Anticancer Res. 2010 Dec;30(12):5011-4.
• [7] Mus81 knockdown sensitizes colon cancer cells to chemotherapeutic drugs by activating CHK1 pathway.Clin Res Hepatol Gastroenterol. 2017 Oct;41(5):592-601. doi: 10.1016/j.clinre.2017.01.011. Epub 2017 Mar 11.
• [8] MUS81 Inhibition Increases the Sensitivity to Therapy Effect in Epithelial Ovarian Cancer via Regulating CyclinB Pathway.J Cancer. 2019 May 21;10(10):2276-2287. doi: 10.7150/jca.30818. eCollection 2019.
• [9] Translational study identifies XPF and MUS81 as predictive biomarkers for oxaliplatin-based peri-operative chemotherapy in patients with esophageal adenocarcinoma.Sci Rep. 2018 May 8;8(1):7265. doi: 10.1038/s41598-018-24232-2.
• [10] Mus81 knockdown improves chemosensitivity of hepatocellular carcinoma cells by inducing S-phase arrest and promoting apoptosis through CHK1 pathway.Cancer Med. 2016 Feb;5(2):370-85. doi: 10.1002/cam4.588. Epub 2015 Dec 29.
• [11] Inhibition of MUS81 improves the chemical sensitivity of olaparib by regulating MCM2 in epithelial ovarian cancer.Oncol Rep. 2018 Apr;39(4):1747-1756. doi: 10.3892/or.2018.6229. Epub 2018 Jan 22.
• [12] MUS81 is associated with cell proliferation and cisplatin sensitivity in serous ovarian cancer.Biochem Biophys Res Commun. 2016 Aug 5;476(4):493-500. doi: 10.1016/j.bbrc.2016.05.152. Epub 2016 May 30.
• [13] The structure-specific endonuclease Mus81 contributes to replication restart by generating double-strand DNA breaks.Nat Struct Mol Biol. 2007 Nov;14(11):1096-104. doi: 10.1038/nsmb1313. Epub 2007 Oct 14.
• [14] The DNA Endonuclease Mus81 Regulates ZEB1 Expression and Serves as a Target of BET4 Inhibitors in Gastric Cancer.Mol Cancer Ther. 2019 Aug;18(8):1439-1450. doi: 10.1158/1535-7163.MCT-18-0833. Epub 2019 May 29.
• [15] 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.
• [16] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [17] 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.
• [18] Arsenic-induced sumoylation of Mus81 is involved in regulating genomic stability. Cell Cycle. 2017 Apr 18;16(8):802-811. doi: 10.1080/15384101.2017.1302628. Epub 2017 Mar 20.
• [19] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] 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.