Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF3WLIM)

• DOT Name: Protein pelota homolog (PELO)
• Synonyms: hPelota; Protein Dom34 homolog
• Gene Name: PELO
• Related Disease: Non-insulin dependent diabetes
• UniProt ID: PELO_HUMAN
• PDB ID: 1X52; 5EO3; 5LZW; 5LZX; 5LZY; 5LZZ
• Pfam ID: PF03463 ; PF03464 ; PF03465
• Sequence:
  MKLVRKNIEKDNAGQVTLVPEEPEDMWHTYNLVQVGDSLRASTIRKVQTESSTGSVGSNR
  VRTTLTLCVEAIDFDSQACQLRVKGTNIQENEYVKMGAYHTIELEPNRQFTLAKKQWDSV
  VLERIEQACDPAWSADVAAVVMQEGLAHICLVTPSMTLTRAKVEVNIPRKRKGNCSQHDR
  ALERFYEQVVQAIQRHIHFDVVKCILVASPGFVREQFCDYLFQQAVKTDNKLLLENRSKF
  LQVHASSGHKYSLKEALCDPTVASRLSDTKAAGEVKALDDFYKMLQHEPDRAFYGLKQVE
  KANEAMAIDTLLISDELFRHQDVATRSRYVRLVDSVKENAGTVRIFSSLHVSGEQLSQLT
  GVAAILRFPVPELSDQEGDSSSEED
• Function: Component of the Pelota-HBS1L complex, a complex that recognizes stalled ribosomes and triggers the No-Go Decay (NGD) pathway. In the Pelota-HBS1L complex, PELO recognizes ribosomes stalled at the 3' end of an mRNA and engages stalled ribosomes by destabilizing mRNA in the mRNA channel. Following mRNA extraction from stalled ribosomes by the SKI complex, the Pelota-HBS1L complex promotes recruitment of ABCE1, which drives the disassembly of stalled ribosomes, followed by degradation of damaged mRNAs as part of the NGD pathway. As part of the PINK1-regulated signaling, upon mitochondrial damage is recruited to the ribosome/mRNA-ribonucleoprotein complex associated to mitochondrial outer membrane thereby enabling the recruitment of autophagy receptors and induction of mitophagy.
• Tissue Specificity: Ubiquitously expressed.
• KEGG Pathway: mR. surveillance pathway (hsa03015)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Vinblastine	DM5TVS3	Approved	Protein pelota homolog (PELO) affects the response to substance of Vinblastine.	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Protein pelota homolog (PELO).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein pelota homolog (PELO).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Protein pelota homolog (PELO).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Protein pelota homolog (PELO).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Protein pelota homolog (PELO).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein pelota homolog (PELO).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Protein pelota homolog (PELO).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein pelota homolog (PELO).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Protein pelota homolog (PELO).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Protein pelota homolog (PELO).	[10]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Protein pelota homolog (PELO).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Protein pelota homolog (PELO).	[12]
Etoposide	DMNH3PG	Approved	Etoposide decreases the expression of Protein pelota homolog (PELO).	[7]
Mitomycin	DMH0ZJE	Approved	Mitomycin decreases the expression of Protein pelota homolog (PELO).	[7]
Colchicine	DM2POTE	Approved	Colchicine decreases the expression of Protein pelota homolog (PELO).	[7]
Hydroxyurea	DMOQVU9	Approved	Hydroxyurea decreases the expression of Protein pelota homolog (PELO).	[7]
Adenine	DMZLHKJ	Approved	Adenine decreases the expression of Protein pelota homolog (PELO).	[7]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Protein pelota homolog (PELO).	[13]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Protein pelota homolog (PELO).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Protein pelota homolog (PELO).	[3]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Protein pelota homolog (PELO).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Protein pelota homolog (PELO).	[15]

References

• [1] Identification of 28 new susceptibility loci for type 2 diabetes in the Japanese population.Nat Genet. 2019 Mar;51(3):379-386. doi: 10.1038/s41588-018-0332-4. Epub 2019 Feb 4.
• [2] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [3] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [4] The RET oncogene is a critical component of transcriptional programs associated with retinoic acid-induced differentiation in neuroblastoma. Mol Cancer Ther. 2007 Apr;6(4):1300-9.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Utilization of CDKN1A/p21 gene for class discrimination of DNA damage-induced clastogenicity. Toxicology. 2014 Jan 6;315:8-16. doi: 10.1016/j.tox.2013.10.009. Epub 2013 Nov 6.
• [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] 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.
• [10] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [11] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [12] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [15] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [16] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.