Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP7Z38L)

• DOT Name: Barrier-to-autointegration factor (BANF1)
• Synonyms: Breakpoint cluster region protein 1
• Gene Name: BANF1
• Related Disease:
  Intellectual disability-sparse hair-brachydactyly syndrome
  Autism
  Carcinoma of esophagus
  Cervical cancer
  Cervical carcinoma
  Colorectal carcinoma
  Esophageal cancer
  Esophageal squamous cell carcinoma
  Ewing sarcoma
  Hutchinson-Gilford progeria syndrome
  Intellectual disability
  Muscular dystrophy
  Neoplasm
  Neoplasm of esophagus
  Nestor-Guillermo progeria syndrome
  Neurodevelopmental disorder
  Noonan syndrome 2
  Premature aging syndrome
  Synovial sarcoma
  Cockayne syndrome
  Hirschsprung disease
  Lung cancer
  Lung carcinoma
  DOORS syndrome
  Non-insulin dependent diabetes
  Advanced cancer
  Anca-associated vasculitis
  Coffin-Siris syndrome
  Gastric cancer
  Malignant neoplasm
  Malignant rhabdoid tumour
  Malignant soft tissue neoplasm
  Microscopic polyangiitis
  Nervous system disease
  Sarcoma
  Stomach cancer
• UniProt ID: BAF_HUMAN
• PDB ID: 1CI4; 1QCK; 2BZF; 2EZX; 2EZY; 2EZZ; 2ODG; 6GHD; 6RPR; 6UNT; 6URE; 6URJ; 6URK; 6URL; 6URN; 6URR; 6URZ; 6US0; 6US1; 6US7; 6USB; 6USD; 6USI; 7ABM; 7NDY; 7Z21
• Pfam ID: PF02961
• Sequence:
  MTTSQKHRDFVAEPMGEKPVGSLAGIGEVLGKKLEERGFDKAYVVLGQFLVLKKDEDLFR
  EWLKDTCGANAKQSRDCFGCLREWCDAFL
• Function: Non-specific DNA-binding protein that plays key roles in mitotic nuclear reassembly, chromatin organization, DNA damage response, gene expression and intrinsic immunity against foreign DNA. Contains two non-specific double-stranded DNA (dsDNA)-binding sites which promote DNA cross-bridging. Plays a key role in nuclear membrane reformation at the end of mitosis by driving formation of a single nucleus in a spindle-independent manner. Transiently cross-bridges anaphase chromosomes via its ability to bridge distant DNA sites, leading to the formation of a dense chromatin network at the chromosome ensemble surface that limits membranes to the surface. Also acts as a negative regulator of innate immune activation by restricting CGAS activity toward self-DNA upon acute loss of nuclear membrane integrity. Outcompetes CGAS for DNA-binding, thereby preventing CGAS activation and subsequent damaging autoinflammatory responses. Also involved in DNA damage response: interacts with PARP1 in response to oxidative stress, thereby inhibiting the ADP-ribosyltransferase activity of PARP1. Involved in the recognition of exogenous dsDNA in the cytosol: associates with exogenous dsDNA immediately after its appearance in the cytosol at endosome breakdown and is required to avoid autophagy. In case of poxvirus infection, has an antiviral activity by blocking viral DNA replication ; (Microbial infection) Exploited by retroviruses for inhibiting self-destructing autointegration of retroviral DNA, thereby promoting integration of viral DNA into the host chromosome. EMD and BAF are cooperative cofactors of HIV-1 infection. Association of EMD with the viral DNA requires the presence of BAF and viral integrase. The association of viral DNA with chromatin requires the presence of BAF and EMD.
• Tissue Specificity: Widely expressed. Expressed in colon, brain, heart, kidney, liver, lung, ovary, pancreas, placenta, prostate, skeletal muscle, small intestine, spleen and testis. Not detected in thymus and peripheral blood leukocytes.
• Reactome Pathway:
  2-LTR circle formation (R-HSA-164843)
  Integration of viral DNA into host genomic DNA (R-HSA-175567)
  Autointegration results in viral DNA circles (R-HSA-177539)
  APOBEC3G mediated resistance to HIV-1 infection (R-HSA-180689)
  Vpr-mediated nuclear import of PICs (R-HSA-180910)
  Nuclear Envelope Breakdown (R-HSA-2980766)
  Initiation of Nuclear Envelope (NE) Reformation (R-HSA-2995383)
  Integration of provirus (R-HSA-162592)

Molecular Interaction Atlas (MIA) of This DOT

36 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability-sparse hair-brachydactyly syndrome	DISEB2FS	Definitive	Biomarker	[1]
Autism	DISV4V1Z	Strong	Genetic Variation	[2]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[3]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[4]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[5]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[3]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[3]
Ewing sarcoma	DISQYLV3	Strong	Biomarker	[6]
Hutchinson-Gilford progeria syndrome	DISY55BU	Strong	Biomarker	[7]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[8]
Muscular dystrophy	DISJD6P7	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[10]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[3]
Nestor-Guillermo progeria syndrome	DIS5B6O8	Strong	Autosomal recessive	[11]
Neurodevelopmental disorder	DIS372XH	Strong	Genetic Variation	[12]
Noonan syndrome 2	DISTDKUR	Strong	Biomarker	[13]
Premature aging syndrome	DIS51AGT	Strong	Genetic Variation	[14]
Synovial sarcoma	DISEZJS7	Strong	Biomarker	[15]
Cockayne syndrome	DISW6GL2	moderate	Genetic Variation	[16]
Hirschsprung disease	DISUUSM1	moderate	Biomarker	[17]
Lung cancer	DISCM4YA	moderate	Biomarker	[18]
Lung carcinoma	DISTR26C	moderate	Biomarker	[18]
DOORS syndrome	DISMR9ZU	Disputed	Genetic Variation	[19]
Non-insulin dependent diabetes	DISK1O5Z	Disputed	Biomarker	[20]
Advanced cancer	DISAT1Z9	Limited	Genetic Variation	[12]
Anca-associated vasculitis	DISU3CNU	Limited	Biomarker	[21]
Coffin-Siris syndrome	DIS8L03H	Limited	Genetic Variation	[22]
Gastric cancer	DISXGOUK	Limited	Biomarker	[23]
Malignant neoplasm	DISS6SNG	Limited	Genetic Variation	[24]
Malignant rhabdoid tumour	DIS46HZU	Limited	Genetic Variation	[24]
Malignant soft tissue neoplasm	DISTC6NO	Limited	Altered Expression	[25]
Microscopic polyangiitis	DIS74KSO	Limited	Biomarker	[21]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[26]
Sarcoma	DISZDG3U	Limited	Altered Expression	[25]
Stomach cancer	DISKIJSX	Limited	Biomarker	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Barrier-to-autointegration factor (BANF1).	[27]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Barrier-to-autointegration factor (BANF1).	[28]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Barrier-to-autointegration factor (BANF1).	[29]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Barrier-to-autointegration factor (BANF1).	[30]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Barrier-to-autointegration factor (BANF1).	[31]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Barrier-to-autointegration factor (BANF1).	[32]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Barrier-to-autointegration factor (BANF1).	[34]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Barrier-to-autointegration factor (BANF1).	[35]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Barrier-to-autointegration factor (BANF1).	[36]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of Barrier-to-autointegration factor (BANF1).	[37]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Barrier-to-autointegration factor (BANF1).	[33]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Barrier-to-autointegration factor (BANF1).	[33]

References

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• [2] The transcriptional regulator ADNP links the BAF (SWI/SNF) complexes with autism.Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):315-26. doi: 10.1002/ajmg.c.31413. Epub 2014 Aug 28.
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• [4] BANF1 is downregulated by IRF1-regulated microRNA-203 in cervical cancer.PLoS One. 2015 Feb 6;10(2):e0117035. doi: 10.1371/journal.pone.0117035. eCollection 2015.
• [5] ARID1A facilitates KRAS signaling-regulatedenhancer activity in an AP1-dependent manner in colorectal cancer cells.Clin Epigenetics. 2019 Jun 19;11(1):92. doi: 10.1186/s13148-019-0690-5.
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• [7] Nuclear Organization in Stress and Aging.Cells. 2019 Jul 1;8(7):664. doi: 10.3390/cells8070664.
• [8] Expanding the Spectrum of BAF-Related Disorders: De Novo Variants in SMARCC2 Cause a Syndrome with Intellectual Disability and Developmental Delay. Am J Hum Genet. 2019 Jan 3;104(1):164-178. doi: 10.1016/j.ajhg.2018.11.007. Epub 2018 Dec 20.
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• [10] BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design.Nat Chem Biol. 2019 Jul;15(7):672-680. doi: 10.1038/s41589-019-0294-6. Epub 2019 Jun 10.
• [11] Exome sequencing and functional analysis identifies BANF1 mutation as the cause of a hereditary progeroid syndrome. Am J Hum Genet. 2011 May 13;88(5):650-6. doi: 10.1016/j.ajhg.2011.04.010. Epub 2011 May 5.
• [12] The BAF complex in development and disease.Epigenetics Chromatin. 2019 Mar 21;12(1):19. doi: 10.1186/s13072-019-0264-y.
• [13] A Recombinant Respiratory Syncytial Virus Vaccine Candidate Attenuated by a Low-Fusion F Protein Is Immunogenic and Protective against Challenge in Cotton Rats.J Virol. 2016 Jul 27;90(16):7508-7518. doi: 10.1128/JVI.00012-16. Print 2016 Aug 15.
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• [15] Epigenetic ConFUSION: SS18-SSX Fusion Rewires BAF Complex to Activate Bivalent Genes in Synovial Sarcoma.Cancer Cell. 2018 Jun 11;33(6):951-953. doi: 10.1016/j.ccell.2018.05.011.
• [16] Barrier to Autointegration Factor (BANF1): interwoven roles in nuclear structure, genome integrity, innate immunity, stress responses and progeria.Curr Opin Cell Biol. 2015 Jun;34:61-8. doi: 10.1016/j.ceb.2015.05.006. Epub 2015 Jun 10.
• [17] Hirschsprung disease as a yet undescribed phenotype in a patient with ARID1B mutation.Am J Med Genet A. 2016 Dec;170(12):3249-3252. doi: 10.1002/ajmg.a.37861. Epub 2016 Aug 11.
• [18] Loss of function of SWI/SNF chromatin remodeling genes leads to genome instability of human lung cancer.Oncol Rep. 2015 Jan;33(1):283-91. doi: 10.3892/or.2014.3584. Epub 2014 Nov 3.
• [19] Coffin-Siris syndrome and related disorders involving components of the BAF (mSWI/SNF) complex: historical review and recent advances using next generation sequencing.Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):241-51. doi: 10.1002/ajmg.c.31415. Epub 2014 Aug 28.
• [20] Vitamin D Switches BAF Complexes to Protect Cells.Cell. 2018 May 17;173(5):1135-1149.e15. doi: 10.1016/j.cell.2018.04.013. Epub 2018 May 10.
• [21] Molecular targeted therapies for microscopic polyangiitis and granulomatosis with polyangiitis.Korean J Intern Med. 2019 May;34(3):492-503. doi: 10.3904/kjim.2018.366. Epub 2019 Jan 9.
• [22] Expanding the phenotypic spectrum associated with DPF2: A new case report.Am J Med Genet A. 2019 Aug;179(8):1637-1641. doi: 10.1002/ajmg.a.61262. Epub 2019 Jun 17.
• [23] Barrier-to-autointegration factor 1: A novel biomarker for gastric cancer.Oncol Lett. 2018 Nov;16(5):6488-6494. doi: 10.3892/ol.2018.9432. Epub 2018 Sep 11.
• [24] SMARCB1 is required for widespread BAF complex-mediated activation of enhancers and bivalent promoters.Nat Genet. 2017 Nov;49(11):1613-1623. doi: 10.1038/ng.3958. Epub 2017 Sep 25.
• [25] Disruption of mammalian SWI/SNF and polycomb complexes in human sarcomas: mechanisms and therapeutic opportunities.J Pathol. 2018 Apr;244(5):638-649. doi: 10.1002/path.5042. Epub 2018 Mar 6.
• [26] Dominant-negative SMARCA4 mutants alter the accessibility landscape of tissue-unrestricted enhancers.Nat Struct Mol Biol. 2018 Jan;25(1):61-72. doi: 10.1038/s41594-017-0007-3. Epub 2017 Dec 11.
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• [28] 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.
• [29] 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.
• [30] 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.
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• [32] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [33] 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.
• [34] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [35] Proteomics and disease network associations evaluation of environmentally relevant Bisphenol A concentrations in a human 3D neural stem cell model. Front Cell Dev Biol. 2023 Aug 16;11:1236243. doi: 10.3389/fcell.2023.1236243. eCollection 2023.
• [36] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [37] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.