Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2H7NXV)

• DOT Name: Pumilio homolog 2 (PUM2)
• Synonyms: Pumilio-2
• Gene Name: PUM2
• Related Disease:
  Adult glioblastoma
  Cervical cancer
  Cervical carcinoma
  Epilepsy
  Glioblastoma multiforme
  Male infertility
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Neoplasm
  Osteosarcoma
• UniProt ID: PUM2_HUMAN
• PDB ID: 3Q0Q; 3Q0R; 3Q0S
• Pfam ID: PF00806
• Sequence:
  MNHDFQALALESRGMGELLPTKKFWEPDDSTKDGQKGIFLGDDEWRETAWGASHHSMSQP
  IMVQRRSGQGFHGNSEVNAILSPRSESGGLGVSMVEYVLSSSPADKLDSRFRKGNFGTRD
  AETDGPEKGDQKGKASPFEEDQNRDLKQGDDDDSKINGRGLPNGMDADCKDFNRTPGSRQ
  ASPTEVVERLGPNTNPSEGLGPLPNPTANKPLVEEFSNPETQNLDAMEQVGLESLQFDYP
  GNQVPMDSSGATVGLFDYNSQQQLFQRTNALTVQQLTAAQQQQYALAAAQQPHIAGVFSA
  GLAPAAFVPNPYIISAAPPGTDPYTAAGLAAAATLAGPAVVPPQYYGVPWGVYPANLFQQ
  QAAAAANNTASQQAASQAQPGQQQVLRAGAGQRPLTPNQGQQGQQAESLAAAAAANPTLA
  FGQGLATGMPGYQVLAPTAYYDQTGALVVGPGARTGLGAPVRLMAPTPVLISSAAAQAAA
  AAAAGGTASSLTGSTNGLFRPIGTQPPQQQQQQPSTNLQSNSFYGSSSLTNSSQSSSLFS
  HGPGQPGSTSLGFGSGNSLGAAIGSALSGFGSSVGSSASSSATRRESLSTSSDLYKRSSS
  SLAPIGQPFYNSLGFSSSPSPIGMPLPSQTPGHSLTPPPSLSSHGSSSSLHLGGLTNGSG
  RYISAAPGAEAKYRSASSTSSLFSSSSQLFPPSRLRYNRSDIMPSGRSRLLEDFRNNRFP
  NLQLRDLIGHIVEFSQDQHGSRFIQQKLERATPAERQMVFNEILQAAYQLMTDVFGNYVI
  QKFFEFGSLDQKLALATRIRGHVLPLALQMYGCRVIQKALESISSDQQVISEMVKELDGH
  VLKCVKDQNGNHVVQKCIECVQPQSLQFIIDAFKGQVFVLSTHPYGCRVIQRILEHCTAE
  QTLPILEELHQHTEQLVQDQYGNYVIQHVLEHGRPEDKSKIVSEIRGKVLALSQHKFASN
  VVEKCVTHASRAERALLIDEVCCQNDGPHSALYTMMKDQYANYVVQKMIDMAEPAQRKII
  MHKIRPHITTLRKYTYGKHILAKLEKYYLKNSPDLGPIGGPPNGML
• Function: Sequence-specific RNA-binding protein that acts as a post-transcriptional repressor by binding the 3'-UTR of mRNA targets. Binds to an RNA consensus sequence, the Pumilio Response Element (PRE), 5'-UGUANAUA-3', that is related to the Nanos Response Element (NRE) (, PubMed:21397187). Mediates post-transcriptional repression of transcripts via different mechanisms: acts via direct recruitment of the CCR4-POP2-NOT deadenylase leading to translational inhibition and mRNA degradation. Also mediates deadenylation-independent repression by promoting accessibility of miRNAs. Acts as a post-transcriptional repressor of E2F3 mRNAs by binding to its 3'-UTR and facilitating miRNA regulation. Plays a role in cytoplasmic sensing of viral infection. Represses a program of genes necessary to maintain genomic stability such as key mitotic, DNA repair and DNA replication factors. Its ability to repress those target mRNAs is regulated by the lncRNA NORAD (non-coding RNA activated by DNA damage) which, due to its high abundance and multitude of PUMILIO binding sites, is able to sequester a significant fraction of PUM1 and PUM2 in the cytoplasm. May regulate DCUN1D3 mRNA levels. May support proliferation and self-renewal of stem cells. Binds specifically to miRNA MIR199A precursor, with PUM1, regulates miRNA MIR199A expression at a postranscriptional level.
• Tissue Specificity: Expressed in male germ cells of adult testis (at protein level). Highly expressed in testis and ovary. Predominantly expressed in stem cells and germ cells. Expressed at lower level in brain, heart, kidney, liver, muscle, placenta, intestine and stomach Expressed in cerebellum, corpus callosum, caudate nucleus, hippocampus, medulla oblongata and putamen. Expressed in all fetal tissues tested.
• KEGG Pathway: Spinocerebellar ataxia (hsa05017)
• Reactome Pathway: Neddylation (R-HSA-8951664)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[1]
Cervical cancer	DISFSHPF	Strong	Biomarker	[2]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[2]
Epilepsy	DISBB28L	Strong	Biomarker	[3]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[1]
Male infertility	DISY3YZZ	Strong	Genetic Variation	[4]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[5]
Breast cancer	DIS7DPX1	Limited	Biomarker	[6]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[6]
Neoplasm	DISZKGEW	Limited	Biomarker	[5]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[5]

3 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 Pumilio homolog 2 (PUM2).	[7]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Pumilio homolog 2 (PUM2).	[15]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Pumilio homolog 2 (PUM2).	[15]

9 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 Pumilio homolog 2 (PUM2).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Pumilio homolog 2 (PUM2).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Pumilio homolog 2 (PUM2).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Pumilio homolog 2 (PUM2).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Pumilio homolog 2 (PUM2).	[12]
Aspirin	DM672AH	Approved	Aspirin increases the expression of Pumilio homolog 2 (PUM2).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Pumilio homolog 2 (PUM2).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Pumilio homolog 2 (PUM2).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Pumilio homolog 2 (PUM2).	[17]

References

• [1] PUM2 Promotes Glioblastoma Cell Proliferation and Migration via Repressing BTG1 Expression.Cell Struct Funct. 2019;44(1):29-39. doi: 10.1247/csf.18030.
• [2] LncRNA TUG1 aggravates the progression of cervical cancer by binding PUM2.Eur Rev Med Pharmacol Sci. 2019 Oct;23(19):8211-8218. doi: 10.26355/eurrev_201910_19128.
• [3] Pumilio2-deficient mice show a predisposition for epilepsy.Dis Model Mech. 2017 Nov 1;10(11):1333-1342. doi: 10.1242/dmm.029678. Epub 2017 Oct 18.
• [4] Polymorphisms of the human PUMILIO2 gene and male sterility.Mol Reprod Dev. 2007 Jun;74(6):795-9. doi: 10.1002/mrd.20683.
• [5] RNA-binding protein PUM2 suppresses osteosarcoma progression via partly and competitively binding to STARD13 3'UTR with miRNAs.Cell Prolif. 2018 Dec;51(6):e12508. doi: 10.1111/cpr.12508. Epub 2018 Aug 7.
• [6] RNA binding protein PUM2 promotes the stemness of breast cancer cells via competitively binding to neuropilin-1 (NRP-1) mRNA with miR-376a.Biomed Pharmacother. 2019 Jun;114:108772. doi: 10.1016/j.biopha.2019.108772. Epub 2019 Mar 23.
• [7] 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.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] 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.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] 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.
• [13] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [14] 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.
• [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.
• [16] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [17] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.