Details of Drug Off-Target (DOT)

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

• DOT Name: Cleavage and polyadenylation specificity factor subunit 5 (NUDT21)
• Synonyms: Cleavage and polyadenylation specificity factor 25 kDa subunit; CPSF 25 kDa subunit; Cleavage factor Im complex 25 kDa subunit; CFIm25; Nucleoside diphosphate-linked moiety X motif 21; Nudix motif 21; Nudix hydrolase 21; Pre-mRNA cleavage factor Im 68 kDa subunit
• Gene Name: NUDT21
• Related Disease:
  Lung cancer
  Lung carcinoma
  Adult glioblastoma
  Advanced cancer
  Bone osteosarcoma
  Hepatocellular carcinoma
  Lung adenocarcinoma
  Malignant glioma
  Neoplasm
  Osteosarcoma
  Bladder cancer
  Pulmonary fibrosis
  Urinary bladder cancer
  Urinary bladder neoplasm
  Glioblastoma multiforme
  Intellectual disability
  leukaemia
  Leukemia
• UniProt ID: CPSF5_HUMAN
• PDB ID: 2CL3; 2J8Q; 3BAP; 3BHO; 3MDG; 3MDI; 3N9U; 3P5T; 3P6Y; 3Q2S; 3Q2T; 5R4P; 5R4Q; 5R4R; 5R4S; 5R4T; 5R4U; 5R64; 5R65; 5R66; 5R67
• Pfam ID: PF13869
• Sequence:
  MSVVPPNRSQTGWPRGVTQFGNKYIQQTKPLTLERTINLYPLTNYTFGTKEPLYEKDSSV
  AARFQRMREEFDKIGMRRTVEGVLIVHEHRLPHVLLLQLGTTFFKLPGGELNPGEDEVEG
  LKRLMTEILGRQDGVLQDWVIDDCIGNWWRPNFEPPQYPYIPAHITKPKEHKKLFLVQLQ
  EKALFAVPKNYKLVAAPLFELYDNAPGYGPIISSLPQLLSRFNFIYN
• Function: Component of the cleavage factor Im (CFIm) complex that functions as an activator of the pre-mRNA 3'-end cleavage and polyadenylation processing required for the maturation of pre-mRNA into functional mRNAs. CFIm contributes to the recruitment of multiprotein complexes on specific sequences on the pre-mRNA 3'-end, so called cleavage and polyadenylation signals (pA signals). Most pre-mRNAs contain multiple pA signals, resulting in alternative cleavage and polyadenylation (APA) producing mRNAs with variable 3'-end formation. The CFIm complex acts as a key regulator of cleavage and polyadenylation site choice during APA through its binding to 5'-UGUA-3' elements localized in the 3'-untranslated region (UTR) for a huge number of pre-mRNAs. NUDT21/CPSF5 activates indirectly the mRNA 3'-processing machinery by recruiting CPSF6 and/or CPSF7. Binds to 5'-UGUA-3' elements localized upstream of pA signals that act as enhancers of pre-mRNA 3'-end processing. The homodimer mediates simultaneous sequence-specific recognition of two 5'-UGUA-3' elements within the pre-mRNA. Plays a role in somatic cell fate transitions and pluripotency by regulating widespread changes in gene expression through an APA-dependent function. Binds to chromatin. Binds to, but does not hydrolyze mono- and di-adenosine nucleotides.
• Tissue Specificity: Expressed in the heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.
• KEGG Pathway: mR. surveillance pathway (hsa03015)
• Reactome Pathway:
  Processing of Capped Intron-Containing Pre-mRNA (R-HSA-72203)
  RNA Polymerase II Transcription Termination (R-HSA-73856)
  Processing of Intronless Pre-mRNAs (R-HSA-77595)
  mRNA 3'-end processing (R-HSA-72187)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung cancer	DISCM4YA	Definitive	Biomarker	[1]
Lung carcinoma	DISTR26C	Definitive	Biomarker	[1]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[6]
Malignant glioma	DISFXKOV	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[4]
Bladder cancer	DISUHNM0	moderate	Altered Expression	[7]
Pulmonary fibrosis	DISQKVLA	moderate	Altered Expression	[8]
Urinary bladder cancer	DISDV4T7	moderate	Altered Expression	[7]
Urinary bladder neoplasm	DIS7HACE	moderate	Altered Expression	[7]
Glioblastoma multiforme	DISK8246	Limited	Altered Expression	[2]
Intellectual disability	DISMBNXP	Limited	Biomarker	[9]
leukaemia	DISS7D1V	Limited	Biomarker	[4]
Leukemia	DISNAKFL	Limited	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Cleavage and polyadenylation specificity factor subunit 5 (NUDT21).	[10]
Arsenic	DMTL2Y1	Approved	Arsenic increases the ubiquitination of Cleavage and polyadenylation specificity factor subunit 5 (NUDT21).	[16]

13 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 Cleavage and polyadenylation specificity factor subunit 5 (NUDT21).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cleavage and polyadenylation specificity factor subunit 5 (NUDT21).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cleavage and polyadenylation specificity factor subunit 5 (NUDT21).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Cleavage and polyadenylation specificity factor subunit 5 (NUDT21).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cleavage and polyadenylation specificity factor subunit 5 (NUDT21).	[15]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Cleavage and polyadenylation specificity factor subunit 5 (NUDT21).	[17]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Cleavage and polyadenylation specificity factor subunit 5 (NUDT21).	[18]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Cleavage and polyadenylation specificity factor subunit 5 (NUDT21).	[19]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Cleavage and polyadenylation specificity factor subunit 5 (NUDT21).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Cleavage and polyadenylation specificity factor subunit 5 (NUDT21).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cleavage and polyadenylation specificity factor subunit 5 (NUDT21).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Cleavage and polyadenylation specificity factor subunit 5 (NUDT21).	[22]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Cleavage and polyadenylation specificity factor subunit 5 (NUDT21).	[23]

References

• [1] Suppression of cleavage factor Im 25 promotes the proliferation of lung cancer cells through alternative polyadenylation.Biochem Biophys Res Commun. 2018 Sep 5;503(2):856-862. doi: 10.1016/j.bbrc.2018.06.087. Epub 2018 Jun 23.
• [2] Nudt21 regulates the alternative polyadenylation of Pak1 and is predictive in the prognosis of glioblastoma patients.Oncogene. 2019 May;38(21):4154-4168. doi: 10.1038/s41388-019-0714-9. Epub 2019 Jan 31.
• [3] CFIm25 and alternative polyadenylation: Conflicting roles in cancer.Cancer Lett. 2019 Sep 10;459:112-121. doi: 10.1016/j.canlet.2019.114430. Epub 2019 Jun 7.
• [4] Knockdown of NUDT21 inhibits proliferation and promotes apoptosis of human K562 leukemia cells through ERK pathway.Cancer Manag Res. 2018 Oct 8;10:4311-4323. doi: 10.2147/CMAR.S173496. eCollection 2018.
• [5] NUDT21 regulates circRNA cyclization and ceRNA crosstalk in hepatocellular carcinoma.Oncogene. 2020 Jan;39(4):891-904. doi: 10.1038/s41388-019-1030-0. Epub 2019 Sep 30.
• [6] c-Myc targeted regulators of cell metabolism in a transgenic mouse model of papillary lung adenocarcinoma.Oncotarget. 2016 Oct 4;7(40):65514-65539. doi: 10.18632/oncotarget.11804.
• [7] NUDT21 inhibits bladder cancer progression through ANXA2 and LIMK2 by alternative polyadenylation.Theranostics. 2019 Sep 23;9(24):7156-7167. doi: 10.7150/thno.36030. eCollection 2019.
• [8] Cleavage factor 25 deregulation contributes to pulmonary fibrosis through alternative polyadenylation.J Clin Invest. 2019 Feb 28;129(5):1984-1999. doi: 10.1172/JCI122106. Print 2019 May 1.
• [9] NUDT21-spanning CNVs lead to neuropsychiatric disease and altered MeCP2 abundance via alternative polyadenylation.Elife. 2015 Aug 27;4:e10782. doi: 10.7554/eLife.10782.
• [10] 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.
• [11] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [12] 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.
• [13] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [14] 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.
• [15] 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.
• [16] Quantitative Assessment of Arsenite-Induced Perturbation of Ubiquitinated Proteome. Chem Res Toxicol. 2022 Sep 19;35(9):1589-1597. doi: 10.1021/acs.chemrestox.2c00197. Epub 2022 Aug 22.
• [17] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [18] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [19] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [20] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [21] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [23] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.