Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLB56HX)

• DOT Name: Histone-binding protein RBBP7 (RBBP7)
• Synonyms: Histone acetyltransferase type B subunit 2; Nucleosome-remodeling factor subunit RBAP46; Retinoblastoma-binding protein 7; RBBP-7; Retinoblastoma-binding protein p46
• Gene Name: RBBP7
• Related Disease:
  X-linked intellectual disability
  Advanced cancer
  Brain neoplasm
  Breast cancer
  Breast carcinoma
  Childhood kidney Wilms tumor
  Esophageal squamous cell carcinoma
  Hepatocellular carcinoma
  Neoplasm
  Wilms tumor
  Breast neoplasm
  Nance-Horan syndrome
  Retinoblastoma
  Rhabdomyosarcoma
• UniProt ID: RBBP7_HUMAN
• PDB ID: 3CFS; 3CFV; 7M3X
• Pfam ID: PF12265 ; PF00400
• Sequence:
  MASKEMFEDTVEERVINEEYKIWKKNTPFLYDLVMTHALQWPSLTVQWLPEVTKPEGKDY
  ALHWLVLGTHTSDEQNHLVVARVHIPNDDAQFDASHCDSDKGEFGGFGSVTGKIECEIKI
  NHEGEVNRARYMPQNPHIIATKTPSSDVLVFDYTKHPAKPDPSGECNPDLRLRGHQKEGY
  GLSWNSNLSGHLLSASDDHTVCLWDINAGPKEGKIVDAKAIFTGHSAVVEDVAWHLLHES
  LFGSVADDQKLMIWDTRSNTTSKPSHLVDAHTAEVNCLSFNPYSEFILATGSADKTVALW
  DLRNLKLKLHTFESHKDEIFQVHWSPHNETILASSGTDRRLNVWDLSKIGEEQSAEDAED
  GPPELLFIHGGHTAKISDFSWNPNEPWVICSVSEDNIMQIWQMAENIYNDEESDVTTSEL
  EGQGS
• Function: Core histone-binding subunit that may target chromatin remodeling factors, histone acetyltransferases and histone deacetylases to their histone substrates in a manner that is regulated by nucleosomal DNA. Component of several complexes which regulate chromatin metabolism. These include the type B histone acetyltransferase (HAT) complex, which is required for chromatin assembly following DNA replication; the core histone deacetylase (HDAC) complex, which promotes histone deacetylation and consequent transcriptional repression; the nucleosome remodeling and histone deacetylase complex (the NuRD complex), which promotes transcriptional repression by histone deacetylation and nucleosome remodeling; and the PRC2/EED-EZH2 complex, which promotes repression of homeotic genes during development; and the NURF (nucleosome remodeling factor) complex.
• KEGG Pathway:
  ATP-dependent chromatin remodeling (hsa03082)
  Polycomb repressive complex (hsa03083)
• Reactome Pathway:
  Oxidative Stress Induced Senescence (R-HSA-2559580)
  HDACs deacetylate histones (R-HSA-3214815)
  PKMTs methylate histone lysines (R-HSA-3214841)
  HATs acetylate histones (R-HSA-3214847)
  RMTs methylate histone arginines (R-HSA-3214858)
  ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression (R-HSA-427389)
  Activation of anterior HOX genes in hindbrain development during early embryogenesis (R-HSA-5617472)
  Deposition of new CENPA-containing nucleosomes at the centromere (R-HSA-606279)
  Regulation of TP53 Activity through Acetylation (R-HSA-6804758)
  RNA Polymerase I Transcription Initiation (R-HSA-73762)
  Regulation of PTEN gene transcription (R-HSA-8943724)
  Neddylation (R-HSA-8951664)
  Transcriptional Regulation by E2F6 (R-HSA-8953750)
  HCMV Early Events (R-HSA-9609690)
  Potential therapeutics for SARS (R-HSA-9679191)
  Defective pyroptosis (R-HSA-9710421)
  PRC2 methylates histones and DNA (R-HSA-212300)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
X-linked intellectual disability	DISYJBY3	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Brain neoplasm	DISY3EKS	Strong	Altered Expression	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Childhood kidney Wilms tumor	DIS0NMK3	Strong	Altered Expression	[5]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Wilms tumor	DISB6T16	Strong	Altered Expression	[5]
Breast neoplasm	DISNGJLM	Limited	Altered Expression	[7]
Nance-Horan syndrome	DISSFYUP	Limited	Genetic Variation	[8]
Retinoblastoma	DISVPNPB	Limited	Biomarker	[7]
Rhabdomyosarcoma	DISNR7MS	Limited	Altered Expression	[9]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	Histone-binding protein RBBP7 (RBBP7) increases the Cell death ADR of Etoposide.	[25]
Hydrocortisone	DMGEMB7	Approved	Histone-binding protein RBBP7 (RBBP7) affects the response to substance of Hydrocortisone.	[5]

14 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 Histone-binding protein RBBP7 (RBBP7).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Histone-binding protein RBBP7 (RBBP7).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Histone-binding protein RBBP7 (RBBP7).	[12]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Histone-binding protein RBBP7 (RBBP7).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Histone-binding protein RBBP7 (RBBP7).	[14]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Histone-binding protein RBBP7 (RBBP7).	[15]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Histone-binding protein RBBP7 (RBBP7).	[16]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Histone-binding protein RBBP7 (RBBP7).	[17]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Histone-binding protein RBBP7 (RBBP7).	[13]
Mitomycin	DMH0ZJE	Approved	Mitomycin increases the expression of Histone-binding protein RBBP7 (RBBP7).	[18]
Promegestone	DMK4S8I	Approved	Promegestone increases the expression of Histone-binding protein RBBP7 (RBBP7).	[19]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of Histone-binding protein RBBP7 (RBBP7).	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Histone-binding protein RBBP7 (RBBP7).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Histone-binding protein RBBP7 (RBBP7).	[24]

3 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 increases the methylation of Histone-binding protein RBBP7 (RBBP7).	[20]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Histone-binding protein RBBP7 (RBBP7).	[22]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Histone-binding protein RBBP7 (RBBP7).	[23]

References

• [1] Characterization of the gene encoding mouse retinoblastoma binding protein-7, a component of chromatin-remodeling complexes.Genomics. 2002 Oct;80(4):407-15. doi: 10.1006/geno.2002.6844.
• [2] RBBP7 is a prognostic biomarker in patients with esophageal squamous cell carcinoma.Oncol Lett. 2018 Dec;16(6):7204-7211. doi: 10.3892/ol.2018.9543. Epub 2018 Oct 3.
• [3] Clinical significance of Polycomb gene expression in brain tumors.Mol Cancer. 2010 Sep 30;9:265. doi: 10.1186/1476-4598-9-265.
• [4] Aberrant expression of X-linked genes RbAp46, Rsk4, and Cldn2 in breast cancer.Mol Cancer Res. 2007 Feb;5(2):171-81. doi: 10.1158/1541-7786.MCR-06-0071.
• [5] Overexpression of RbAp46 facilitates stress-induced apoptosis and suppresses tumorigenicity of neoplastigenic breast epithelial cells. Int J Cancer. 2003 Jul 20;105(6):762-8. doi: 10.1002/ijc.11148.
• [6] Long-Read RNA Sequencing Identifies Alternative Splice Variants in Hepatocellular Carcinoma and Tumor-Specific Isoforms.Hepatology. 2019 Sep;70(3):1011-1025. doi: 10.1002/hep.30500. Epub 2019 Mar 22.
• [7] The role of retinoblastoma-associated proteins 46 and 48 in estrogen receptor alpha mediated gene expression.Mol Cell Endocrinol. 2008 Sep 10;291(1-2):79-86. doi: 10.1016/j.mce.2008.05.016. Epub 2008 Jun 5.
• [8] Refinement of the X-linked cataract locus (CXN) and gene analysis for CXN and Nance-Horan syndrome (NHS).Ophthalmic Genet. 2004 Jun;25(2):121-31. doi: 10.1080/13816810490514360.
• [9] High expression of EZH2 as a marker for the differential diagnosis of malignant and benign myogenic tumors.Sci Rep. 2018 Aug 17;8(1):12331. doi: 10.1038/s41598-018-30648-7.
• [10] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [11] 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.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Comparative gene expression profiling reveals partially overlapping but distinct genomic actions of different antiestrogens in human breast cancer cells. J Cell Biochem. 2006 Aug 1;98(5):1163-84.
• [14] 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.
• [15] 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.
• [16] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [17] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [18] Genomic and proteomic profiling of responses to toxic metals in human lung cells. Environ Health Perspect. 2003 May;111(6):825-35.
• [19] Short-chain fatty acids enhance nuclear receptor activity through mitogen-activated protein kinase activation and histone deacetylase inhibition. Proc Natl Acad Sci U S A. 2004 May 4;101(18):7199-204.
• [20] 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.
• [21] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [22] 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.
• [23] 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.
• [24] 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.
• [25] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [26] Overexpression of RbAp46 facilitates stress-induced apoptosis and suppresses tumorigenicity of neoplastigenic breast epithelial cells. Int J Cancer. 2003 Jul 20;105(6):762-8. doi: 10.1002/ijc.11148.