Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN5HE0W)

• DOT Name: Protein downstream neighbor of Son (DONSON)
• Synonyms: B17
• Gene Name: DONSON
• Related Disease:
  Colorectal carcinoma
  Colorectal neoplasm
  Fanconi anemia complementation group A
  Fanconi's anemia
  Gastric cancer
  Microcephaly, short stature, and limb abnormalities
  Microlissencephaly
  Seckel syndrome
  Stomach cancer
  Isolated congenital microcephaly
  Psoriasis
• UniProt ID: DONS_HUMAN
• Sequence:
  MALSVPGYSPGFRKPPEVVRLRRKRARSRGAAASPPRELTEPAARRAALVAGLPLRPFPA
  AGGRGGGSGGGPAAARRNPFARLDNRPRVAAEPPDGPAREQPEAPVPFLDSNQENDLLWE
  EKFPERTTVTELPQTSHVSFSEPDIPSSKSTELPVDWSIKTRLLFTSSQPFTWADHLKAQ
  EEAQGLVQHCRATEVTLPKSIQDPKLSSELRCTFQQSLIYWLHPALSWLPLFPRIGADRK
  MAGKTSPWSNDATLQHVLMSDWSVSFTSLYNLLKTKLCPYFYVCTYQFTVLFRAAGLAGS
  DLITALISPTTRGLREAMRNEGIEFSLPLIKESGHKKETASGTSLGYGEEQAISDEDEEE
  SFSWLEEMGVQDKIKKPDILSIKLRKEKHEVQMDHRPESVVLVKGINTFTLLNFLINSKS
  LVATSGPQAGLPPTLLSPVAFRGATMQMLKARSVNVKTQALSGYRDQFSLEITGPIMPHS
  LHSLTMLLKSSQSGSFSAVLYPHEPTAVFNICLQMDKVLDMEVVHKELTNCGLHPNTLEQ
  LSQIPLLGKSSLRNVVLRDYIYNWRS
• Function: Replisome component that maintains genome stability by protecting stalled or damaged replication forks. After the induction of replication stress, required for the stabilization of stalled replication forks, the efficient activation of the intra-S-phase and G/2M cell-cycle checkpoints and the maintenance of genome stability.
• Tissue Specificity: Expressed in the brain, with higher levels in prenatal compared to adult brain.

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal carcinoma	DIS5PYL0	Definitive	Biomarker	[1]
Colorectal neoplasm	DISR1UCN	Definitive	Biomarker	[1]
Fanconi anemia complementation group A	DIS8PZLI	Strong	Genetic Variation	[2]
Fanconi's anemia	DISGW6Q8	Strong	Genetic Variation	[2]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[3]
Microcephaly, short stature, and limb abnormalities	DISHW9OU	Strong	Autosomal recessive	[4]
Microlissencephaly	DISUCKNT	Strong	Biomarker	[5]
Seckel syndrome	DISEVUBA	Strong	Genetic Variation	[2]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[3]
Isolated congenital microcephaly	DISUXHZ6	moderate	Genetic Variation	[6]
Psoriasis	DIS59VMN	Limited	Genetic Variation	[7]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Vinblastine	DM5TVS3	Approved	Protein downstream neighbor of Son (DONSON) affects the response to substance of Vinblastine.	[22]

15 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 Protein downstream neighbor of Son (DONSON).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein downstream neighbor of Son (DONSON).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Protein downstream neighbor of Son (DONSON).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Protein downstream neighbor of Son (DONSON).	[11]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Protein downstream neighbor of Son (DONSON).	[12]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Protein downstream neighbor of Son (DONSON).	[12]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Protein downstream neighbor of Son (DONSON).	[13]
Piroxicam	DMTK234	Approved	Piroxicam increases the expression of Protein downstream neighbor of Son (DONSON).	[14]
Palbociclib	DMD7L94	Approved	Palbociclib decreases the expression of Protein downstream neighbor of Son (DONSON).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Protein downstream neighbor of Son (DONSON).	[16]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Protein downstream neighbor of Son (DONSON).	[11]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Protein downstream neighbor of Son (DONSON).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Protein downstream neighbor of Son (DONSON).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein downstream neighbor of Son (DONSON).	[19]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Protein downstream neighbor of Son (DONSON).	[11]

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 Protein downstream neighbor of Son (DONSON).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Protein downstream neighbor of Son (DONSON).	[21]

References

• [1] Highly Expressed Genes in Rapidly Proliferating Tumor Cells as New Targets for Colorectal Cancer Treatment.Clin Cancer Res. 2015 Aug 15;21(16):3695-704. doi: 10.1158/1078-0432.CCR-14-2457. Epub 2015 May 5.
• [2] Microcephaly, short stature, and limb abnormality disorder due to novel autosomal biallelic DONSON mutations in two German siblings.Eur J Hum Genet. 2018 Sep;26(9):1282-1287. doi: 10.1038/s41431-018-0128-0. Epub 2018 May 14.
• [3] Circular RNA circ-DONSON facilitates gastric cancer growth and invasion via NURF complex dependent activation of transcription factor SOX4.Mol Cancer. 2019 Mar 28;18(1):45. doi: 10.1186/s12943-019-1006-2.
• [4] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [5] Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism. Nat Genet. 2017 Apr;49(4):537-549. doi: 10.1038/ng.3790. Epub 2017 Feb 13.
• [6] Biallelic and De Novo Variants in DONSON Reveal a Clinical Spectrum of Cell Cycle-opathies with Microcephaly, Dwarfism and Skeletal Abnormalities.Am J Med Genet A. 2019 Oct;179(10):2056-2066. doi: 10.1002/ajmg.a.61315. Epub 2019 Aug 13.
• [7] Whole-exome SNP array identifies 15 new susceptibility loci for psoriasis.Nat Commun. 2015 Apr 9;6:6793. doi: 10.1038/ncomms7793.
• [8] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [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] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [11] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [12] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [15] Cdk4/6 inhibition induces epithelial-mesenchymal transition and enhances invasiveness in pancreatic cancer cells. Mol Cancer Ther. 2012 Oct;11(10):2138-48. doi: 10.1158/1535-7163.MCT-12-0562. Epub 2012 Aug 6.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [18] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.