Details of Drug Off-Target (DOT)

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

• DOT Name: Serrate RNA effector molecule homolog (SRRT)
• Synonyms: Arsenite-resistance protein 2
• Gene Name: SRRT
• Related Disease:
  Adult glioblastoma
  Bipolar disorder
  Cholangiocarcinoma
  Congenital contractural arachnodactyly
  Hepatocellular carcinoma
  Major depressive disorder
  Neoplasm
  Schizophrenia
  Glioblastoma multiforme
• UniProt ID: SRRT_HUMAN
• PDB ID: 5OO6; 6F7J; 6F7P; 6F7S; 6F8D
• Pfam ID: PF04959 ; PF12066
• Sequence:
  MGDSDDEYDRRRRDKFRRERSDYDRSRERDERRRGDDWNDREWDRGRERRSRGEYRDYDR
  NRRERFSPPRHELSPPQKRMRRDWDEHSSDPYHSGYEMPYAGGGGGPTYGPPQPWGHPDV
  HIMQHHVLPIQARLGSIAEIDLGVPPPVMKTFKEFLLSLDDSVDETEAVKRYNDYKLDFR
  RQQMQDFFLAHKDEEWFRSKYHPDEVGKRRQEARGALQNRLRVFLSLMETGWFDNLLLDI
  DKADAIVKMLDAAVIKMEGGTENDLRILEQEEEEEQAGKPGEPSKKEEGRAGAGLGDGER
  KTNDKDEKKEDGKQAENDSSNDDKTKKSEGDGDKEEKKEDSEKEAKKSSKKRNRKHSGDD
  SFDEGSVSESESESESGQAEEEKEEAEEALKEKEKPKEEEWEKPKDAAGLECKPRPLHKT
  CSLFMRNIAPNISRAEIISLCKRYPGFMRVALSEPQPERRFFRRGWVTFDRSVNIKEICW
  NLQNIRLRECELSPGVNRDLTRRVRNINGITQHKQIVRNDIKLAAKLIHTLDDRTQLWAS
  EPGTPPLPTSLPSQNPILKNITDYLIEEVSAEEEELLGSSGGAPPEEPPKEGNPAEINVE
  RDEKLIKVLDKLLLYLRIVHSLDYYNTCEYPNEDEMPNRCGIIHVRGPMPPNRISHGEVL
  EWQKTFEEKLTPLLSVRESLSEEEAQKMGRKDPEQEVEKFVTSNTQELGKDKWLCPLSGK
  KFKGPEFVRKHIFNKHAEKIEEVKKEVAFFNNFLTDAKRPALPEIKPAQPPGPAQILPPG
  LTPGLPYPHQTPQGLMPYGQPRPPILGYGAGAVRPAVPTGGPPYPHAPYGAGRGNYDAFR
  GQGGYPGKPRNRMVRGDPRAIVEYRDLDAPDDVDFF
• Function: Acts as a mediator between the cap-binding complex (CBC) and the primary microRNAs (miRNAs) processing machinery during cell proliferation. Contributes to the stability and delivery of capped primary miRNA transcripts to the primary miRNA processing complex containing DGCR8 and DROSHA, thereby playing a role in RNA-mediated gene silencing (RNAi) by miRNAs. Binds capped RNAs (m7GpppG-capped RNA); however interaction is probably mediated via its interaction with NCBP1/CBP80 component of the CBC complex. Involved in cell cycle progression at S phase. Does not directly confer arsenite resistance but rather modulates arsenic sensitivity. Independently of its activity on miRNAs, necessary and sufficient to promote neural stem cell self-renewal. Does so by directly binding SOX2 promoter and positively regulating its transcription.
• Tissue Specificity: Ubiquitously expressed.
• Reactome Pathway:
  mRNA Splicing - Major Pathway (R-HSA-72163)
  RNA polymerase II transcribes snRNA genes (R-HSA-6807505)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[1]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[2]
Cholangiocarcinoma	DIS71F6X	Strong	Altered Expression	[3]
Congenital contractural arachnodactyly	DISOM1K7	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[4]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Schizophrenia	DISSRV2N	Strong	Biomarker	[2]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Serrate RNA effector molecule homolog (SRRT).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Serrate RNA effector molecule homolog (SRRT).	[12]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Serrate RNA effector molecule homolog (SRRT).	[15]

9 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 Serrate RNA effector molecule homolog (SRRT).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Serrate RNA effector molecule homolog (SRRT).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Serrate RNA effector molecule homolog (SRRT).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Serrate RNA effector molecule homolog (SRRT).	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Serrate RNA effector molecule homolog (SRRT).	[10]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Serrate RNA effector molecule homolog (SRRT).	[11]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Serrate RNA effector molecule homolog (SRRT).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Serrate RNA effector molecule homolog (SRRT).	[14]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Serrate RNA effector molecule homolog (SRRT).	[7]

References

• [1] Knockdown of arsenic resistance protein 2 inhibits human glioblastoma cell proliferation through the MAPK/ERK pathway.Oncol Rep. 2018 Dec;40(6):3313-3322. doi: 10.3892/or.2018.6777. Epub 2018 Oct 9.
• [2] Construction and analysis of the protein-protein interaction networks for schizophrenia, bipolar disorder, and major depression.BMC Bioinformatics. 2011;12 Suppl 13(Suppl 13):S20. doi: 10.1186/1471-2105-12-S13-S20. Epub 2011 Nov 30.
• [3] Ars2 is overexpressed in human cholangiocarcinomas and its depletion increases PTEN and PDCD4 by decreasing microRNA-21.Mol Carcinog. 2013 Apr;52(4):286-96. doi: 10.1002/mc.21859. Epub 2011 Dec 28.
• [4] Expression and prognostic value of Ars2 in hepatocellular carcinoma.Int J Clin Oncol. 2014 Oct;19(5):880-8. doi: 10.1007/s10147-013-0642-6. Epub 2013 Nov 23.
• [5] 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.
• [6] Pharmacogenomic analysis of acute promyelocytic leukemia cells highlights CYP26 cytochrome metabolism in differential all-trans retinoic acid sensitivity. Blood. 2007 May 15;109(10):4450-60.
• [7] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [8] 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.
• [9] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [10] 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.
• [11] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [12] 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.
• [13] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [14] 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.
• [15] 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.