Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSMGH99)

• DOT Name: Non-histone chromosomal protein HMG-14 (HMGN1)
• Synonyms: High mobility group nucleosome-binding domain-containing protein 1
• Gene Name: HMGN1
• Related Disease:
  Autoimmune disease
  Diabetic kidney disease
  Promyelocytic leukaemia
  Renal fibrosis
  Systemic lupus erythematosus
  Trichohepatoenteric syndrome
  Ventricular septal defect
  Anxiety
  Anxiety disorder
  Autism
  Autism spectrum disorder
  Bone osteosarcoma
  Neurodevelopmental disorder
  Osteosarcoma
  Neoplasm
• UniProt ID: HMGN1_HUMAN
• Pfam ID: PF01101
• Sequence:
  MPKRKVSSAEGAAKEEPKRRSARLSAKPPAKVEAKPKKAAAKDKSSDKKVQTKGKRGAKG
  KQAEVANQETKEDLPAENGETKTEESPASDEAGEKEAKSD
• Function: Binds to the inner side of the nucleosomal DNA thus altering the interaction between the DNA and the histone octamer. May be involved in the process which maintains transcribable genes in a unique chromatin conformation. Inhibits the phosphorylation of nucleosomal histones H3 and H2A by RPS6KA5/MSK1 and RPS6KA3/RSK2.
• Reactome Pathway:
  Transcription-Coupled Nucleotide Excision Repair (TC-NER) (R-HSA-6781827)
  Dual incision in TC-NER (R-HSA-6782135)
  Gap-filling DNA repair synthesis and ligation in TC-NER (R-HSA-6782210)
  Formation of TC-NER Pre-Incision Complex (R-HSA-6781823)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autoimmune disease	DISORMTM	Strong	Biomarker	[1]
Diabetic kidney disease	DISJMWEY	Strong	Altered Expression	[2]
Promyelocytic leukaemia	DISYGG13	Strong	Altered Expression	[3]
Renal fibrosis	DISMHI3I	Strong	Biomarker	[2]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[1]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Biomarker	[4]
Ventricular septal defect	DISICO41	Strong	Biomarker	[5]
Anxiety	DISIJDBA	moderate	Altered Expression	[6]
Anxiety disorder	DISBI2BT	moderate	Altered Expression	[6]
Autism	DISV4V1Z	moderate	Genetic Variation	[6]
Autism spectrum disorder	DISXK8NV	moderate	Altered Expression	[6]
Bone osteosarcoma	DIST1004	moderate	Biomarker	[7]
Neurodevelopmental disorder	DIS372XH	moderate	Biomarker	[6]
Osteosarcoma	DISLQ7E2	moderate	Biomarker	[7]
Neoplasm	DISZKGEW	Limited	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Non-histone chromosomal protein HMG-14 (HMGN1).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Non-histone chromosomal protein HMG-14 (HMGN1).	[10]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Non-histone chromosomal protein HMG-14 (HMGN1).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Non-histone chromosomal protein HMG-14 (HMGN1).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Non-histone chromosomal protein HMG-14 (HMGN1).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Non-histone chromosomal protein HMG-14 (HMGN1).	[17]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of Non-histone chromosomal protein HMG-14 (HMGN1).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Non-histone chromosomal protein HMG-14 (HMGN1).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Non-histone chromosomal protein HMG-14 (HMGN1).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Non-histone chromosomal protein HMG-14 (HMGN1).	[15]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Non-histone chromosomal protein HMG-14 (HMGN1).	[15]

References

• [1] Primary pulmonary hypertension: immunogenetic response to high-mobility group (HMG) proteins and histone.Clin Exp Immunol. 1996 Nov;106(2):389-95. doi: 10.1046/j.1365-2249.1996.d01-848.x.
• [2] High-Mobility Group Nucleosome-Binding Protein 1 Mediates Renal Fibrosis Correlating with Macrophages Accumulation and Epithelial-to-Mesenchymal Transition in Diabetic Nephropathy Mice Model.Kidney Blood Press Res. 2019;44(3):331-343. doi: 10.1159/000499877. Epub 2019 Jun 14.
• [3] Expression of chromosomal proteins HMG-14 and HMG-17 in transformed human cells.Cancer Res. 1990 Apr 1;50(7):2022-6.
• [4] Chromosomal protein HMG-14 gene maps to the Down syndrome region of human chromosome 21 and is overexpressed in mouse trisomy 16.Proc Natl Acad Sci U S A. 1990 May;87(10):3836-40. doi: 10.1073/pnas.87.10.3836.
• [5] Heterotrisomy, a significant contributing factor to ventricular septal defect associated with Down syndrome?.Hum Genet. 2000 Nov;107(5):476-82. doi: 10.1007/s004390000395.
• [6] The chromatin-binding protein HMGN1 regulates the expression of methyl CpG-binding protein 2 (MECP2) and affects the behavior of mice.J Biol Chem. 2011 Dec 9;286(49):42051-42062. doi: 10.1074/jbc.M111.300541. Epub 2011 Oct 17.
• [7] Nucleosome-binding protein HMGN2 exhibits antitumor activity in human SaO2 and U2-OS osteosarcoma cell lines.Oncol Rep. 2015 Mar;33(3):1300-6. doi: 10.3892/or.2014.3689. Epub 2014 Dec 22.
• [8] Development of a Curative Therapeutic Vaccine (TheraVac) for the Treatment of Large Established Tumors.Sci Rep. 2017 Oct 27;7(1):14186. doi: 10.1038/s41598-017-14655-8.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.
• [12] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [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] 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.
• [15] 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.
• [16] 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.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [18] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.