Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC93H3S)

• DOT Name: DNA helicase MCM8 (MCM8)
• Synonyms: EC 3.6.4.12; Minichromosome maintenance 8
• Gene Name: MCM8
• Related Disease:
  B-cell neoplasm
  Breast cancer
  Breast carcinoma
  Female hypogonadism
  Haematological malignancy
  Lung adenocarcinoma
  Malignant neoplasm
  Pancreatic cancer
  Premature ovarian failure 10
  Prostate cancer
  Prostate carcinoma
  Uterine fibroids
  Choriocarcinoma
  Colon adenocarcinoma
  Hepatocellular carcinoma
  Neoplasm
  Advanced cancer
• UniProt ID: MCM8_HUMAN
• PDB ID: 6L0O; 7DP3; 7WI7; 7YOX; 8S91; 8S92; 8S94
• EC Number: 3.6.4.12
• Pfam ID: PF00493 ; PF17855 ; PF17207
• Sequence:
  MNGEYRGRGFGRGRFQSWKRGRGGGNFSGKWREREHRPDLSKTTGKRTSEQTPQFLLSTK
  TPQSMQSTLDRFIPYKGWKLYFSEVYSDSSPLIEKIQAFEKFFTRHIDLYDKDEIERKGS
  ILVDFKELTEGGEVTNLIPDIATELRDAPEKTLACMGLAIHQVLTKDLERHAAELQAQEG
  LSNDGETMVNVPHIHARVYNYEPLTQLKNVRANYYGKYIALRGTVVRVSNIKPLCTKMAF
  LCAACGEIQSFPLPDGKYSLPTKCPVPVCRGRSFTALRSSPLTVTMDWQSIKIQELMSDD
  QREAGRIPRTIECELVHDLVDSCVPGDTVTITGIVKVSNAEEGSRNKNDKCMFLLYIEAN
  SISNSKGQKTKSSEDGCKHGMLMEFSLKDLYAIQEIQAEENLFKLIVNSLCPVIFGHELV
  KAGLALALFGGSQKYADDKNRIPIRGDPHILVVGDPGLGKSQMLQAACNVAPRGVYVCGN
  TTTTSGLTVTLSKDSSSGDFALEAGALVLGDQGICGIDEFDKMGNQHQALLEAMEQQSIS
  LAKAGVVCSLPARTSIIAAANPVGGHYNKAKTVSENLKMGSALLSRFDLVFILLDTPNEH
  HDHLLSEHVIAIRAGKQRTISSATVARMNSQDSNTSVLEVVSEKPLSERLKVVPGETIDP
  IPHQLLRKYIGYARQYVYPRLSTEAARVLQDFYLELRKQSQRLNSSPITTRQLESLIRLT
  EARARLELREEATKEDAEDIVEIMKYSMLGTYSDEFGNLDFERSQHGSGMSNRSTAKRFI
  SALNNVAERTYNNIFQFHQLRQIAKELNIQVADFENFIGSLNDQGYLLKKGPKVYQLQTM
• Function: Component of the MCM8-MCM9 complex, a complex involved in the repair of double-stranded DNA breaks (DBSs) and DNA interstrand cross-links (ICLs) by homologous recombination (HR). Required for DNA resection by the MRE11-RAD50-NBN/NBS1 (MRN) complex by recruiting the MRN complex to the repair site and by promoting the complex nuclease activity. Probably by regulating the localization of the MNR complex, indirectly regulates the recruitment of downstream effector RAD51 to DNA damage sites including DBSs and ICLs. The MCM8-MCM9 complex is dispensable for DNA replication and S phase progression. However, may play a non-essential for DNA replication: may be involved in the activation of the prereplicative complex (pre-RC) during G(1) phase by recruiting CDC6 to the origin recognition complex (ORC). Probably by regulating HR, plays a key role during gametogenesis. Stabilizes MCM9 protein.
• Tissue Specificity: Highest levels in placenta, lung and pancreas. Low levels in skeletal muscle and kidney. Expressed in various tumors with highest levels in colon and lung cancers.
• Reactome Pathway:
  Activation of ATR in response to replication stress (R-HSA-176187)
  Unwinding of DNA (R-HSA-176974)
  CDC6 association with the ORC (R-HSA-68689)
  Orc1 removal from chromatin (R-HSA-68949)
  Activation of the pre-replicative complex (R-HSA-68962)
  E2F-enabled inhibition of pre-replication complex formation (R-HSA-113507)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell neoplasm	DISVY326	Strong	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[2]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[2]
Female hypogonadism	DISWASB4	Strong	Genetic Variation	[3]
Haematological malignancy	DISCDP7W	Strong	Biomarker	[4]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[5]
Malignant neoplasm	DISS6SNG	Strong	Genetic Variation	[6]
Pancreatic cancer	DISJC981	Strong	Biomarker	[7]
Premature ovarian failure 10	DIS27KD8	Strong	Autosomal recessive	[8]
Prostate cancer	DISF190Y	Strong	Altered Expression	[9]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[9]
Uterine fibroids	DISBZRMJ	Strong	Genetic Variation	[10]
Choriocarcinoma	DISDBVNL	moderate	Biomarker	[11]
Colon adenocarcinoma	DISDRE0J	moderate	Altered Expression	[11]
Hepatocellular carcinoma	DIS0J828	moderate	Altered Expression	[12]
Neoplasm	DISZKGEW	moderate	Altered Expression	[11]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of DNA helicase MCM8 (MCM8).	[14]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of DNA helicase MCM8 (MCM8).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of DNA helicase MCM8 (MCM8).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of DNA helicase MCM8 (MCM8).	[28]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of DNA helicase MCM8 (MCM8).	[27]

16 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 DNA helicase MCM8 (MCM8).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DNA helicase MCM8 (MCM8).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of DNA helicase MCM8 (MCM8).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of DNA helicase MCM8 (MCM8).	[18]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of DNA helicase MCM8 (MCM8).	[20]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of DNA helicase MCM8 (MCM8).	[21]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of DNA helicase MCM8 (MCM8).	[21]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of DNA helicase MCM8 (MCM8).	[22]
Etoposide	DMNH3PG	Approved	Etoposide decreases the expression of DNA helicase MCM8 (MCM8).	[23]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of DNA helicase MCM8 (MCM8).	[24]
Lucanthone	DMZLBUO	Approved	Lucanthone decreases the expression of DNA helicase MCM8 (MCM8).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of DNA helicase MCM8 (MCM8).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of DNA helicase MCM8 (MCM8).	[26]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of DNA helicase MCM8 (MCM8).	[29]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of DNA helicase MCM8 (MCM8).	[30]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE increases the expression of DNA helicase MCM8 (MCM8).	[23]

References

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• [2] Variants associating with uterine leiomyoma highlight genetic background shared by various cancers and hormone-related traits.Nat Commun. 2018 Sep 7;9(1):3636. doi: 10.1038/s41467-018-05428-6.
• [3] The MCM8/9 complex: A recent recruit to the roster of helicases involved in genome maintenance.DNA Repair (Amst). 2019 Apr;76:1-10. doi: 10.1016/j.dnarep.2019.02.003. Epub 2019 Feb 5.
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• [8] MCM8- and MCM9-deficient mice reveal gametogenesis defects and genome instability due to impaired homologous recombination. Mol Cell. 2012 Aug 24;47(4):523-34. doi: 10.1016/j.molcel.2012.05.048. Epub 2012 Jul 5.
• [9] Oncogenic activity of amplified miniature chromosome maintenance 8 in human malignancies.Oncogene. 2017 Jun 22;36(25):3629-3639. doi: 10.1038/onc.2017.123. Epub 2017 May 8.
• [10] Genome-wide association and epidemiological analyses reveal common genetic origins between uterine leiomyomata and endometriosis.Nat Commun. 2019 Oct 24;10(1):4857. doi: 10.1038/s41467-019-12536-4.
• [11] A new member of the MCM protein family encoded by the human MCM8 gene, located contrapodal to GCD10 at chromosome band 20p12.3-13.Nucleic Acids Res. 2003 Jun 1;31(11):2915-25. doi: 10.1093/nar/gkg395.
• [12] MCM family in HCC: MCM6 indicates adverse tumor features and poor outcomes and promotes S/G2 cell cycle progression.BMC Cancer. 2018 Feb 20;18(1):200. doi: 10.1186/s12885-018-4056-8.
• [13] Inhibiting the MCM8-9 complex selectively sensitizes cancer cells to cisplatin and olaparib.Cancer Sci. 2019 Mar;110(3):1044-1053. doi: 10.1111/cas.13941. Epub 2019 Feb 14.
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• [18] 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.
• [19] 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.
• [20] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [21] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [22] Cannabidiol-induced transcriptomic changes and cellular senescence in human Sertoli cells. Toxicol Sci. 2023 Feb 17;191(2):227-238. doi: 10.1093/toxsci/kfac131.
• [23] Responses of genes involved in cell cycle control to diverse DNA damaging chemicals in human lung adenocarcinoma A549 cells. Cancer Cell Int. 2005 Aug 24;5:28. doi: 10.1186/1475-2867-5-28.
• [24] 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.
• [25] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [26] 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.
• [27] 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.
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• [29] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [30] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.