Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQNZTE4)

• DOT Name: Nuclear cap-binding protein subunit 2 (NCBP2)
• Synonyms: 20 kDa nuclear cap-binding protein; Cell proliferation-inducing gene 55 protein; NCBP 20 kDa subunit; CBP20; NCBP-interacting protein 1; NIP1
• Gene Name: NCBP2
• Related Disease:
  Breast cancer
  Breast carcinoma
  Head-neck squamous cell carcinoma
  Lung cancer
  Lung carcinoma
• UniProt ID: NCBP2_HUMAN
• PDB ID: 1H2T; 1H2U; 1H2V; 1H6K; 1N52; 1N54; 3FEX; 3FEY; 5OO6; 5OOB; 6D0Y; 7ABG
• Pfam ID: PF00076
• Sequence:
  MSGGLLKALRSDSYVELSQYRDQHFRGDNEEQEKLLKKSCTLYVGNLSFYTTEEQIYELF
  SKSGDIKKIIMGLDKMKKTACGFCFVEYYSRADAENAMRYINGTRLDDRIIRTDWDAGFK
  EGRQYGRGRSGGQVRDEYRQDYDAGRGGYGKLAQNQ
• Function: Component of the cap-binding complex (CBC), which binds co-transcriptionally to the 5' cap of pre-mRNAs and is involved in various processes such as pre-mRNA splicing, translation regulation, nonsense-mediated mRNA decay, RNA-mediated gene silencing (RNAi) by microRNAs (miRNAs) and mRNA export. The CBC complex is involved in mRNA export from the nucleus via its interaction with ALYREF/THOC4/ALY, leading to the recruitment of the mRNA export machinery to the 5' end of mRNA and to mRNA export in a 5' to 3' direction through the nuclear pore. The CBC complex is also involved in mediating U snRNA and intronless mRNAs export from the nucleus. The CBC complex is essential for a pioneer round of mRNA translation, before steady state translation when the CBC complex is replaced by cytoplasmic cap-binding protein eIF4E. The pioneer round of mRNA translation mediated by the CBC complex plays a central role in nonsense-mediated mRNA decay (NMD), NMD only taking place in mRNAs bound to the CBC complex, but not on eIF4E-bound mRNAs. The CBC complex enhances NMD in mRNAs containing at least one exon-junction complex (EJC) via its interaction with UPF1, promoting the interaction between UPF1 and UPF2. The CBC complex is also involved in 'failsafe' NMD, which is independent of the EJC complex, while it does not participate in Staufen-mediated mRNA decay (SMD). During cell proliferation, the CBC complex is also involved in microRNAs (miRNAs) biogenesis via its interaction with SRRT/ARS2, thereby being required for miRNA-mediated RNA interference. The CBC complex also acts as a negative regulator of PARN, thereby acting as an inhibitor of mRNA deadenylation. In the CBC complex, NCBP2/CBP20 recognizes and binds capped RNAs (m7GpppG-capped RNA) but requires NCBP1/CBP80 to stabilize the movement of its N-terminal loop and lock the CBC into a high affinity cap-binding state with the cap structure. The conventional cap-binding complex with NCBP2 binds both small nuclear RNA (snRNA) and messenger (mRNA) and is involved in their export from the nucleus.
• KEGG Pathway:
  Nucleocytoplasmic transport (hsa03013)
  mR. surveillance pathway (hsa03015)
  Spliceosome (hsa03040)
• Reactome Pathway:
  Formation of RNA Pol II elongation complex (R-HSA-112382)
  Formation of the Early Elongation Complex (R-HSA-113418)
  Transport of the SLBP independent Mature mRNA (R-HSA-159227)
  Transport of the SLBP Dependant Mature mRNA (R-HSA-159230)
  Transport of Mature mRNA Derived from an Intronless Transcript (R-HSA-159231)
  Transport of Mature mRNA derived from an Intron-Containing Transcript (R-HSA-159236)
  Formation of HIV elongation complex in the absence of HIV Tat (R-HSA-167152)
  Formation of the HIV-1 Early Elongation Complex (R-HSA-167158)
  Formation of HIV-1 elongation complex containing HIV-1 Tat (R-HSA-167200)
  Abortive elongation of HIV-1 transcript in the absence of Tat (R-HSA-167242)
  snRNP Assembly (R-HSA-191859)
  RNA Polymerase II Pre-transcription Events (R-HSA-674695)
  FGFR2 alternative splicing (R-HSA-6803529)
  RNA polymerase II transcribes snRNA genes (R-HSA-6807505)
  mRNA Capping (R-HSA-72086)
  mRNA Splicing - Major Pathway (R-HSA-72163)
  mRNA Splicing - Minor Pathway (R-HSA-72165)
  mRNA 3'-end processing (R-HSA-72187)
  Processing of Capped Intron-Containing Pre-mRNA (R-HSA-72203)
  RNA Polymerase II Transcription Termination (R-HSA-73856)
  SLBP Dependent Processing of Replication-Dependent Histone Pre-mRNAs (R-HSA-77588)
  Processing of Intronless Pre-mRNAs (R-HSA-77595)
  Signaling by FGFR2 IIIa TM (R-HSA-8851708)
  Regulation of expression of SLITs and ROBOs (R-HSA-9010553)
  Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC) (R-HSA-975956)
  Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) (R-HSA-975957)
  SLBP independent Processing of Histone Pre-mRNAs (R-HSA-111367)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[1]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[2]
Lung cancer	DISCM4YA	Limited	Genetic Variation	[3]
Lung carcinoma	DISTR26C	Limited	Genetic Variation	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Nuclear cap-binding protein subunit 2 (NCBP2).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Nuclear cap-binding protein subunit 2 (NCBP2).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Nuclear cap-binding protein subunit 2 (NCBP2).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Nuclear cap-binding protein subunit 2 (NCBP2).	[7]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Nuclear cap-binding protein subunit 2 (NCBP2).	[8]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Nuclear cap-binding protein subunit 2 (NCBP2).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Nuclear cap-binding protein subunit 2 (NCBP2).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Nuclear cap-binding protein subunit 2 (NCBP2).	[10]

References

• [1] NIP1/DUOXA1 expression in epithelial breast cancer cells: regulation of cell adhesion and actin dynamics.Breast Cancer Res Treat. 2010 Feb;119(3):773-86. doi: 10.1007/s10549-009-0372-7. Epub 2009 Mar 26.
• [2] Meta-Analyses of Microarray Datasets Identifies ANO1 and FADD as Prognostic Markers of Head and Neck Cancer.PLoS One. 2016 Jan 25;11(1):e0147409. doi: 10.1371/journal.pone.0147409. eCollection 2016.
• [3] Microarray data re-annotation reveals specific lncRNAs and their potential functions in non-small cell lung cancer subtypes.Mol Med Rep. 2017 Oct;16(4):5129-5136. doi: 10.3892/mmr.2017.7244. Epub 2017 Aug 14.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [6] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [7] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [8] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [9] 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.
• [10] 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.