Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEA6FYJ)

• DOT Name: Mortality factor 4-like protein 1 (MORF4L1)
• Synonyms: MORF-related gene 15 protein; MRG15; Protein MSL3-1; Transcription factor-like protein MRG15
• Gene Name: MORF4L1
• Related Disease:
  Advanced cancer
  Coronary heart disease
  Myocardial infarction
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Lung squamous cell carcinoma
  Myotonic dystrophy type 1
  Nasopharyngeal carcinoma
  Neoplasm
  Pneumonia
• UniProt ID: MO4L1_HUMAN
• PDB ID: 2AQL; 2EFI; 2F5J; 2F5K; 2LKM; 2N1D; 6AGO; 6INE; 7S4A; 8BPA; 8C60
• Pfam ID: PF05712 ; PF11717
• Sequence:
  MAPKQDPKPKFQEGERVLCFHGPLLYEAKCVKVAIKDKQVKYFIHYSGWNKKSAVRPRRS
  EKSLKTHEDIVALFPVPEGAPSVHHPLLTSSWDEWVPESRVLKYVDTNLQKQRELQKANQ
  EQYAEGKMRGAAPGKKTSGLQQKNVEVKTKKNKQKTPGNGDGGSTSETPQPPRKKRARVD
  PTVENEETFMNRVEVKVKIPEELKPWLVDDWDLITRQKQLFYLPAKKNVDSILEDYANYK
  KSRGNTDNKEYAVNEVVAGIKEYFNVMLGTQLLYKFERPQYAEILADHPDAPMSQVYGAP
  HLLRLFVRIGAMLAYTPLDEKSLALLLNYLHDFLKYLAKNSATLFSASDYEVAPPEYHRK
  AV
• Function: Component of the NuA4 histone acetyltransferase (HAT) complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A. This modification may both alter nucleosome - DNA interactions and promote interaction of the modified histones with other proteins which positively regulate transcription. This complex may be required for the activation of transcriptional programs associated with oncogene and proto-oncogene mediated growth induction, tumor suppressor mediated growth arrest and replicative senescence, apoptosis, and DNA repair. The NuA4 complex ATPase and helicase activities seem to be, at least in part, contributed by the association of RUVBL1 and RUVBL2 with EP400. NuA4 may also play a direct role in DNA repair when directly recruited to sites of DNA damage. As part of the SIN3B complex represses transcription and counteracts the histone acetyltransferase activity of EP300 through the recognition H3K27ac marks by PHF12 and the activity of the histone deacetylase HDAC2. SIN3B complex is recruited downstream of the constitutively active genes transcriptional start sites through interaction with histones and mitigates histone acetylation and RNA polymerase II progression within transcribed regions contributing to the regulation of transcription. Required for homologous recombination repair (HRR) and resistance to mitomycin C (MMC). Involved in the localization of PALB2, BRCA2 and RAD51, but not BRCA1, to DNA-damage foci.
• KEGG Pathway: ATP-dependent chromatin remodeling (hsa03082)
• Reactome Pathway: HATs acetylate histones (R-HSA-3214847)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[2]
Myocardial infarction	DIS655KI	moderate	Genetic Variation	[3]
Lung adenocarcinoma	DISD51WR	Limited	Genetic Variation	[4]
Lung cancer	DISCM4YA	Limited	Genetic Variation	[5]
Lung carcinoma	DISTR26C	Limited	Genetic Variation	[4]
Lung squamous cell carcinoma	DISXPIBD	Limited	Genetic Variation	[4]
Myotonic dystrophy type 1	DISJC0OX	Limited	Altered Expression	[6]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Altered Expression	[7]
Neoplasm	DISZKGEW	Limited	Biomarker	[7]
Pneumonia	DIS8EF3M	Limited	Altered Expression	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Mortality factor 4-like protein 1 (MORF4L1).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Mortality factor 4-like protein 1 (MORF4L1).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Mortality factor 4-like protein 1 (MORF4L1).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Mortality factor 4-like protein 1 (MORF4L1).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Mortality factor 4-like protein 1 (MORF4L1).	[14]

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 decreases the methylation of Mortality factor 4-like protein 1 (MORF4L1).	[13]

References

• [1] Targets of genome copy number reduction in primary breast cancers identified by integrative genomics.Genes Chromosomes Cancer. 2007 Mar;46(3):288-301. doi: 10.1002/gcc.20411.
• [2] Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.Circ Res. 2018 Feb 2;122(3):433-443. doi: 10.1161/CIRCRESAHA.117.312086. Epub 2017 Dec 6.
• [3] A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease.Nat Genet. 2015 Oct;47(10):1121-1130. doi: 10.1038/ng.3396. Epub 2015 Sep 7.
• [4] Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.Nat Genet. 2017 Jul;49(7):1126-1132. doi: 10.1038/ng.3892. Epub 2017 Jun 12.
• [5] Influence of common genetic variation on lung cancer risk: meta-analysis of 14 900 cases and 29 485 controls.Hum Mol Genet. 2012 Nov 15;21(22):4980-95. doi: 10.1093/hmg/dds334. Epub 2012 Aug 16.
• [6] Expansion of CUG RNA repeats causes stress and inhibition of translation in myotonic dystrophy 1 (DM1) cells.FASEB J. 2010 Oct;24(10):3706-19. doi: 10.1096/fj.09-151159. Epub 2010 May 17.
• [7] MORF4L1 suppresses cell proliferation, migration and invasion by increasing p21 and E-cadherin expression in nasopharyngeal carcinoma.Oncol Lett. 2019 Jan;17(1):294-302. doi: 10.3892/ol.2018.9588. Epub 2018 Oct 16.
• [8] Mortality factor 4 like 1 protein mediates epithelial cell death in a mouse model of pneumonia.Sci Transl Med. 2015 Oct 28;7(311):311ra171. doi: 10.1126/scitranslmed.aac7793.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [11] 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.
• [12] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [13] 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.
• [14] 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.