Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4S44GP)

• DOT Name: Histone chaperone ASF1A (ASF1A)
• Synonyms: Anti-silencing function protein 1 homolog A; hAsf1; hAsf1a; CCG1-interacting factor A; CIA; hCIA
• Gene Name: ASF1A
• Related Disease:
  Advanced cancer
  Anemia
  Arthritis
  Bone disease
  Breast neoplasm
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Hepatocellular carcinoma
  Leukopenia
  Lung adenocarcinoma
  Melanoma
  Rheumatoid arthritis
  Agranulocytosis
  Neoplasm
• UniProt ID: ASF1A_HUMAN
• PDB ID: 1TEY; 2I32; 2IIJ; 2IO5; 3AAD; 5C3I; 6F0F; 6F0G; 6F0H; 6ZUF; 7LNY; 7LO0; 7V6Q; 8BV1; 8CJ1; 8CJ2; 8CJ3
• Pfam ID: PF04729
• Sequence:
  MAKVQVNNVVVLDNPSPFYNPFQFEITFECIEDLSEDLEWKIIYVGSAESEEYDQVLDSV
  LVGPVPAGRHMFVFQADAPNPGLIPDADAVGVTVVLITCTYRGQEFIRVGYYVNNEYTET
  ELRENPPVKPDFSKLQRNILASNPRVTRFHINWEDNTEKLEDAESSNPNLQSLLSTDALP
  SASKGWSTSENSLNVMLESHMDCM
• Function: Histone chaperone that facilitates histone deposition and histone exchange and removal during nucleosome assembly and disassembly. Cooperates with chromatin assembly factor 1 (CAF-1) to promote replication-dependent chromatin assembly and with HIRA to promote replication-independent chromatin assembly. Promotes homologous recombination-mediated repair of double-strand breaks (DSBs) at stalled or collapsed replication forks: acts by mediating histone replacement at DSBs, leading to recruitment of the MMS22L-TONSL complex and subsequent loading of RAD51. Also involved in the nuclear import of the histone H3-H4 dimer together with importin-4 (IPO4): specifically recognizes and binds newly synthesized histones with the monomethylation of H3 'Lys-9' and acetylation at 'Lys-14' (H3K9me1K14ac) marks, and diacetylation at 'Lys-5' and 'Lys-12' of H4 (H4K5K12ac) marks in the cytosol. Required for the formation of senescence-associated heterochromatin foci (SAHF) and efficient senescence-associated cell cycle exit.
• Tissue Specificity: Ubiquitously expressed.
• Reactome Pathway: Formation of Senescence-Associated Heterochromatin Foci (SAHF) (R-HSA-2559584)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Anemia	DISTVL0C	Strong	Biomarker	[2]
Arthritis	DIST1YEL	Strong	Biomarker	[3]
Bone disease	DISE1F82	Strong	Biomarker	[4]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[5]
Colon cancer	DISVC52G	Strong	Biomarker	[6]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[1]
Leukopenia	DISJMBMM	Strong	Biomarker	[8]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[9]
Melanoma	DIS1RRCY	Strong	Genetic Variation	[10]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[11]
Agranulocytosis	DISJS4LS	Disputed	Genetic Variation	[12]
Neoplasm	DISZKGEW	Limited	Biomarker	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Histone chaperone ASF1A (ASF1A).	[13]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Histone chaperone ASF1A (ASF1A).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Histone chaperone ASF1A (ASF1A).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Histone chaperone ASF1A (ASF1A).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Histone chaperone ASF1A (ASF1A).	[17]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Histone chaperone ASF1A (ASF1A).	[18]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Histone chaperone ASF1A (ASF1A).	[19]
Menadione	DMSJDTY	Approved	Menadione increases the expression of Histone chaperone ASF1A (ASF1A).	[19]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Histone chaperone ASF1A (ASF1A).	[20]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Histone chaperone ASF1A (ASF1A).	[21]
Chlorambucil	DMRKE63	Approved	Chlorambucil decreases the expression of Histone chaperone ASF1A (ASF1A).	[20]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate decreases the expression of Histone chaperone ASF1A (ASF1A).	[20]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of Histone chaperone ASF1A (ASF1A).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Histone chaperone ASF1A (ASF1A).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Histone chaperone ASF1A (ASF1A).	[23]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Histone chaperone ASF1A (ASF1A).	[26]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Histone chaperone ASF1A (ASF1A).	[27]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Histone chaperone ASF1A (ASF1A).	[28]

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 affects the phosphorylation of Histone chaperone ASF1A (ASF1A).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Histone chaperone ASF1A (ASF1A).	[25]

References

• [1] ASF1a inhibition induces p53-dependent growth arrest and senescence of cancer cells.Cell Death Dis. 2019 Jan 28;10(2):76. doi: 10.1038/s41419-019-1357-z.
• [2] Synergetic pathogenicity of Newcastle disease vaccines LaSota strain and contaminated chicken infectious anemia virus.Poult Sci. 2019 May 1;98(5):1985-1992. doi: 10.3382/ps/pey555.
• [3] Combination of gp130-targeting and TNF-targeting small molecules in alleviating arthritis through the down-regulation of Th17 differentiation and osteoclastogenesis.Biochem Biophys Res Commun. 2020 Feb 19;522(4):1030-1036. doi: 10.1016/j.bbrc.2019.11.183. Epub 2019 Dec 6.
• [4] Therapeutic role of a vaccine targeting RANKL and TNF- on collagen-induced arthritis.Biomaterials. 2012 Nov;33(32):8177-85. doi: 10.1016/j.biomaterials.2012.07.047. Epub 2012 Aug 9.
• [5] Asf1b, the necessary Asf1 isoform for proliferation, is predictive of outcome in breast cancer.EMBO J. 2011 Feb 2;30(3):480-93. doi: 10.1038/emboj.2010.335. Epub 2010 Dec 21.
• [6] ASF1A regulates H4(Y72) phosphorylation and promotes autophagy in colon cancer cells via a kinase activity.Artif Cells Nanomed Biotechnol. 2019 Dec;47(1):2754-2763. doi: 10.1080/21691401.2019.1617725.
• [7] Histone Chaperone ASF1A Predicts Poor Outcomes for Patients With Gastrointestinal Cancer and Drives Cancer Progression by Stimulating Transcription of -Catenin Target Genes.EBioMedicine. 2017 Jul;21:104-116. doi: 10.1016/j.ebiom.2017.06.007. Epub 2017 Jun 8.
• [8] Efficacy and Safety of Supportive Care Biosimilars Among Cancer Patients: A Systematic Review and Meta-Analysis.BioDrugs. 2019 Aug;33(4):373-389. doi: 10.1007/s40259-019-00356-3.
• [9] In Vivo Epigenetic CRISPR Screen Identifies Asf1a as an Immunotherapeutic Target in Kras-Mutant Lung Adenocarcinoma.Cancer Discov. 2020 Feb;10(2):270-287. doi: 10.1158/2159-8290.CD-19-0780. Epub 2019 Nov 19.
• [10] Scleral Thinning Documented by Ultrasound Biomicroscopy after Plaque Therapy for Anterior Ciliary Melanoma.Semin Ophthalmol. 2018;33(4):571-575. doi: 10.1080/08820538.2017.1346131. Epub 2017 Jul 13.
• [11] PBT-6, a Novel PI3KC2 Inhibitor in Rheumatoid Arthritis.Biomol Ther (Seoul). 2020 Mar 1;28(2):172-183. doi: 10.4062/biomolther.2019.153.
• [12] Exploring off-targets and off-systems for adverse drug reactions via chemical-protein interactome--clozapine-induced agranulocytosis as a case study.PLoS Comput Biol. 2011 Mar;7(3):e1002016. doi: 10.1371/journal.pcbi.1002016. Epub 2011 Mar 31.
• [13] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [14] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [15] 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.
• [16] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] 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.
• [18] 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.
• [19] Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach. Toxicology. 2013 Apr 5;306:24-34.
• [20] Oxidative stress mechanisms do not discriminate between genotoxic and nongenotoxic liver carcinogens. Chem Res Toxicol. 2015 Aug 17;28(8):1636-46.
• [21] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [22] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [27] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [28] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.