Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ2X3Q4)

• DOT Name: RNA-binding protein Nova-2 (NOVA2)
• Synonyms: Astrocytic NOVA1-like RNA-binding protein; Neuro-oncological ventral antigen 2
• Gene Name: NOVA2
• Related Disease:
  Neoplasm
  Breast cancer
  Breast carcinoma
  High blood pressure
  Neuroblastoma
  Neurodevelopmental disorder with or without autistic features and/or structural brain abnormalities
  Retinoblastoma
  Cognitive impairment
  Nervous system disease
• UniProt ID: NOVA2_HUMAN
• PDB ID: 1DTJ; 1EC6
• Pfam ID: PF00013
• Sequence:
  MEPEAPDSRKRPLETPPEVVCTKRSNTGEEGEYFLKVLIPSYAAGSIIGKGGQTIVQLQK
  ETGATIKLSKSKDFYPGTTERVCLVQGTAEALNAVHSFIAEKVREIPQAMTKPEVVNILQ
  PQTTMNPDRAKQAKLIVPNSTAGLIIGKGGATVKAVMEQSGAWVQLSQKPEGINLQERVV
  TVSGEPEQVHKAVSAIVQKVQEDPQSSSCLNISYANVAGPVANSNPTGSPYASPADVLPA
  AAAASAAAASGLLGPAGLAGVGAFPAALPAFSGTDLLAISTALNTLASYGYNTNSLGLGL
  NSAAASGVLAAVAAGANPAAAAAANLLASYAGEAGAGPAGGAAPPPPPPPGALGSFALAA
  AANGYLGAGAGGGAGGGGGPLVAAAAAAGAAGGFLTAEKLAAESAKELVEIAVPENLVGA
  ILGKGGKTLVEYQELTGARIQISKKGEFLPGTRNRRVTITGSPAATQAAQYLISQRVTYE
  QGVRASNPQKVG
• Function: Functions to regulate alternative splicing in neurons by binding pre-mRNA in a sequence-specific manner to activate exon inclusion or exclusion. It binds specifically to the sequences 5'-YCAY-3' and regulates splicing in only a subset of regulated exons. Binding to an exonic 5'-YCAY-3' cluster changes the protein complexes assembled on pre-mRNA, blocking U1 snRNP binding and exon inclusion, whereas binding to an intronic 5'-YCAY-3' cluster enhances spliceosome assembly and exon inclusion. With NOVA1, they perform unique biological functions in different brain areas and cell types. Uniquely regulates alternative splicing events of a series of axon guidance related genes during cortical development, being essential for central nervous system development by regulating neural networks wiring. Regulates differentially alternative splicing on the same transcripts expressed in different neurons. This includes functional differences in transcripts expressed in cortical and cerebellar excitatory versus inhibitory neurons where is required for, respectively, development of laminar structure and motor coordination and synapse formation. Also the regulation the regulation of intron retention can sequester the trans-acting splicing factor PTBP2, acting as a variable cis-acting scaffolding platform for PTBP2 across various natural conditions.
• Tissue Specificity: Brain. Expression restricted to astrocytes.

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
High blood pressure	DISY2OHH	Strong	Biomarker	[3]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[4]
Neurodevelopmental disorder with or without autistic features and/or structural brain abnormalities	DIS2DJ29	Strong	Autosomal dominant	[5]
Retinoblastoma	DISVPNPB	Strong	Altered Expression	[4]
Cognitive impairment	DISH2ERD	Limited	Altered Expression	[6]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of RNA-binding protein Nova-2 (NOVA2).	[8]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of RNA-binding protein Nova-2 (NOVA2).	[9]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of RNA-binding protein Nova-2 (NOVA2).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of RNA-binding protein Nova-2 (NOVA2).	[11]
UNC0379	DMD1E4J	Preclinical	UNC0379 decreases the expression of RNA-binding protein Nova-2 (NOVA2).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of RNA-binding protein Nova-2 (NOVA2).	[14]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of RNA-binding protein Nova-2 (NOVA2).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of RNA-binding protein Nova-2 (NOVA2).	[12]

References

• [1] A novel L1CAM isoform with angiogenic activity generated by NOVA2-mediated alternative splicing.Elife. 2019 Mar 4;8:e44305. doi: 10.7554/eLife.44305.
• [2] High Satisfaction and Low Distress in Breast Cancer Patients One Year after BRCA-Mutation Testing without Prior Face-to-Face Genetic Counseling.J Genet Couns. 2016 Jun;25(3):504-14. doi: 10.1007/s10897-015-9899-4. Epub 2015 Nov 4.
• [3] Arterial compliance by cuff sphygmomanometer. Application to hypertension and early changes in subjects at genetic risk.Hypertension. 1996 Oct;28(4):599-603. doi: 10.1161/01.hyp.28.4.599.
• [4] Disabled-1 alternative splicing in human fetal retina and neural tumors.PLoS One. 2011;6(12):e28579. doi: 10.1371/journal.pone.0028579. Epub 2011 Dec 6.
• [5] Increased diagnostic and new genes identification outcome using research reanalysis of singleton exome sequencing. Eur J Hum Genet. 2019 Oct;27(10):1519-1531. doi: 10.1038/s41431-019-0442-1. Epub 2019 Jun 23.
• [6] The neuronal RNA-binding protein Nova-2 is implicated as the autoantigen targeted in POMA patients with dementia.Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):13254-9. doi: 10.1073/pnas.95.22.13254.
• [7] Crystal structures of Nova-1 and Nova-2 K-homology RNA-binding domains.Structure. 1999 Feb 15;7(2):191-203. doi: 10.1016/S0969-2126(99)80025-2.
• [8] 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.
• [9] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [10] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [11] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [12] 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.
• [13] Epigenetic siRNA and chemical screens identify SETD8 inhibition as a therapeutic strategy for p53 activation in high-risk neuroblastoma. Cancer Cell. 2017 Jan 9;31(1):50-63.
• [14] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [15] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.