Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGM083T)

• DOT Name: Histone H2B type 1-J (H2BC11)
• Synonyms: Histone H2B.1; Histone H2B.r; H2B/r
• Gene Name: H2BC11
• Related Disease:
  Systemic lupus erythematosus
  Anemia
• UniProt ID: H2B1J_HUMAN
• PDB ID: 2RVQ ; 3A6N ; 3AFA ; 3AN2 ; 3AV1 ; 3AV2 ; 3AYW ; 3AZE ; 3AZF ; 3AZG ; 3AZH ; 3AZI ; 3AZJ ; 3AZK ; 3AZL ; 3AZM ; 3AZN ; 3W96 ; 3W97 ; 3W98 ; 3W99 ; 3WA9 ; 3WAA ; 3WTP ; 4CAY ; 4YM5 ; 4YM6 ; 4Z5T ; 5AV5 ; 5AV6 ; 5AV8 ; 5AV9 ; 5AVB ; 5AVC ; 5AY8 ; 5B0Y ; 5B0Z ; 5B24 ; 5B2I ; 5B2J ; 5B31 ; 5B32 ; 5B33 ; 5B40 ; 5CPI ; 5CPJ ; 5CPK ; 5FUG ; 5GSE ; 5GTC ; 5GXQ ; 5JRG ; 5VEY ; 5X7X ; 5XF3 ; 5XF4 ; 5XF5 ; 5Y0C ; 5Y0D ; 5Z23 ; 5Z30 ; 5ZBX ; 6A5L ; 6A5O ; 6A5P ; 6A5R ; 6A5T ; 6A5U ; 6BUZ ; 6E0C ; 6E0P ; 6HKT ; 6HTS ; 6INQ ; 6IPU ; 6IQ4 ; 6IR9 ; 6J4W ; 6J4X ; 6J4Y ; 6J4Z ; 6J50 ; 6J51 ; 6JOU ; 6JR0 ; 6JR1 ; 6JXD ; 6K1I ; 6K1J ; 6K1K ; 6KVD ; 6KXV ; 6L49 ; 6L4A ; 6L9Z ; 6LA2 ; 6LA8 ; 6LA9 ; 6LAB ; 6LER ; 6M3V ; 6M44 ; 6O1D ; 6R8Y ; 6R8Z ; 6R90 ; 6R91 ; 6R92 ; 6R93 ; 6R94 ; 6T90 ; 6T93 ; 6USJ ; 6V2K ; 6YOV ; 7BY0 ; 7C0M ; 7CCQ ; 7CCR ; 7COW ; 7D1Z ; 7D20 ; 7E8D ; 7K5X ; 7K5Y ; 7K60 ; 7K61 ; 7K63 ; 7LYA ; 7LYB ; 7LYC ; 7NL0 ; 7SCY ; 7SCZ ; 7VCL ; 7VZ4 ; 7W9V ; 7WBV ; 7WBW ; 7WBX ; 7XSE ; 7XSX ; 7XSZ ; 7XT7 ; 7XTD ; 7XTI ; 7XVL ; 7XVM ; 7XX5 ; 7XX6 ; 7XX7 ; 7XZX ; 7XZY ; 7XZZ ; 7Y00 ; 7Y7I ; 7YRD ; 7ZI4 ; 8G57 ; 8GUI ; 8GUJ ; 8GUK ; 8H0V ; 8H0W ; 8HAG ; 8HAH ; 8HAI ; 8HAJ ; 8HAK ; 8HAL ; 8HAM ; 8HAN ; 8HE5 ; 8I17 ; 8JH2 ; 8JH3 ; 8JH4 ; 8JL9 ; 8JLA ; 8JLB ; 8JLD ; 8KB5 ; 8OSJ ; 8OSK ; 8OSL ; 8OTS ; 8OTT ; 8QKT
• Pfam ID: PF00125
• Sequence:
  MPEPAKSAPAPKKGSKKAVTKAQKKDGKKRKRSRKESYSIYVYKVLKQVHPDTGISSKAM
  GIMNSFVNDIFERIAGEASRLAHYNKRSTITSREIQTAVRLLLPGELAKHAVSEGTKAVT
  KYTSAK
• Function: Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.; Has broad antibacterial activity. May contribute to the formation of the functional antimicrobial barrier of the colonic epithelium, and to the bactericidal activity of amniotic fluid.
• KEGG Pathway:
  Neutrophil extracellular trap formation (hsa04613)
  Alcoholism (hsa05034)
  Viral carcinogenesis (hsa05203)
  Systemic lupus erythematosus (hsa05322)
• Reactome Pathway:
  Cleavage of the damaged pyrimidine (R-HSA-110329)
  Recognition and association of DNA glycosylase with site containing an affected purine (R-HSA-110330)
  Cleavage of the damaged purine (R-HSA-110331)
  Meiotic synapsis (R-HSA-1221632)
  Packaging Of Telomere Ends (R-HSA-171306)
  Pre-NOTCH Transcription and Translation (R-HSA-1912408)
  Formation of the beta-catenin (R-HSA-201722)
  PRC2 methylates histones and DNA (R-HSA-212300)
  Condensation of Prophase Chromosomes (R-HSA-2299718)
  Oxidative Stress Induced Senescence (R-HSA-2559580)
  Senescence-Associated Secretory Phenotype (SASP) (R-HSA-2559582)
  DNA Damage/Telomere Stress Induced Senescence (R-HSA-2559586)
  HDACs deacetylate histones (R-HSA-3214815)
  HATs acetylate histones (R-HSA-3214847)
  SIRT1 negatively regulates rRNA expression (R-HSA-427359)
  ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression (R-HSA-427389)
  NoRC negatively regulates rRNA expression (R-HSA-427413)
  B-WICH complex positively regulates rRNA expression (R-HSA-5250924)
  DNA methylation (R-HSA-5334118)
  Transcriptional regulation by small RNAs (R-HSA-5578749)
  Activation of anterior HOX genes in hindbrain development during early embryogenesis (R-HSA-5617472)
  Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 (R-HSA-5625886)
  Ub-specific processing proteases (R-HSA-5689880)
  Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks (R-HSA-5693565)
  Nonhomologous End-Joining (NHEJ) (R-HSA-5693571)
  Processing of DNA double-strand break ends (R-HSA-5693607)
  Deposition of new CENPA-containing nucleosomes at the centromere (R-HSA-606279)
  Assembly of the ORC complex at the origin of replication (R-HSA-68616)
  G2/M DNA damage checkpoint (R-HSA-69473)
  RNA Polymerase I Promoter Opening (R-HSA-73728)
  RNA Polymerase I Promoter Escape (R-HSA-73772)
  E3 ubiquitin ligases ubiquitinate target proteins (R-HSA-8866654)
  RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function (R-HSA-8936459)
  RUNX1 regulates transcription of genes involved in differentiation of HSCs (R-HSA-8939236)
  Estrogen-dependent gene expression (R-HSA-9018519)
  Meiotic recombination (R-HSA-912446)
  HCMV Early Events (R-HSA-9609690)
  HCMV Late Events (R-HSA-9610379)
  Transcriptional regulation of granulopoiesis (R-HSA-9616222)
  Inhibition of DNA recombination at telomere (R-HSA-9670095)
  Defective pyroptosis (R-HSA-9710421)
  Amyloid fiber formation (R-HSA-977225)
  Chromatin modifications during the maternal to zygotic transition (MZT) (R-HSA-9821002)
  Replacement of protamines by nucleosomes in the male pronucleus (R-HSA-9821993)
  Recognition and association of DNA glycosylase with site containing an affected pyrimidine (R-HSA-110328)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[1]
Anemia	DISTVL0C	Limited	Genetic Variation	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Histone H2B type 1-J (H2BC11).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Histone H2B type 1-J (H2BC11).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Histone H2B type 1-J (H2BC11).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Histone H2B type 1-J (H2BC11).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Histone H2B type 1-J (H2BC11).	[7]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Histone H2B type 1-J (H2BC11).	[8]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Histone H2B type 1-J (H2BC11).	[9]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Histone H2B type 1-J (H2BC11).	[10]
Berberine	DMC5Q8X	Phase 4	Berberine decreases the expression of Histone H2B type 1-J (H2BC11).	[11]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 affects the expression of Histone H2B type 1-J (H2BC11).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Histone H2B type 1-J (H2BC11).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Histone H2B type 1-J (H2BC11).	[14]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Histone H2B type 1-J (H2BC11).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Histone H2B type 1-J (H2BC11).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Histone H2B type 1-J (H2BC11).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure affects the expression of Histone H2B type 1-J (H2BC11).	[18]

References

• [1] Identification of a histone family gene signature for predicting the prognosis of cervical cancer patients.Sci Rep. 2017 Nov 28;7(1):16495. doi: 10.1038/s41598-017-16472-5.
• [2] Genetic contribution to iron status: SNPs related to iron deficiency anaemia and fine mapping of CACNA2D3 calcium channel subunit.Blood Cells Mol Dis. 2015 Dec;55(4):273-80. doi: 10.1016/j.bcmd.2015.07.008. Epub 2015 Jul 16.
• [3] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] 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.
• [8] Chronic ethanol exposure increases goosecoid (GSC) expression in human embryonic carcinoma cell differentiation. J Appl Toxicol. 2014 Jan;34(1):66-75.
• [9] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [10] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [11] Berberine acts as a putative epigenetic modulator by affecting the histone code. Toxicol In Vitro. 2016 Oct;36:10-17. doi: 10.1016/j.tiv.2016.06.004. Epub 2016 Jun 13.
• [12] OTX015 (MK-8628), a novel BET inhibitor, displays in vitro and in vivo antitumor effects alone and in combination with conventional therapies in glioblastoma models. Int J Cancer. 2016 Nov 1;139(9):2047-55. doi: 10.1002/ijc.30256. Epub 2016 Jul 30.
• [13] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [14] Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc Natl Acad Sci U S A. 2011 Oct 4;108(40):16669-74. doi: 10.1073/pnas.1108190108. Epub 2011 Sep 26.
• [15] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [16] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [17] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.