Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA3U1N6)

• DOT Name: HBS1-like protein (HBS1L)
• Synonyms: EC 3.6.5.-; ERFS
• Gene Name: HBS1L
• Related Disease:
  Classic Hodgkin lymphoma
  Hepatitis B virus infection
  Benign prostatic hyperplasia
  Beta-thalassemia intermedia
  Cardiac arrest
  Essential thrombocythemia
  Kidney failure
  Polycythemia vera
  Thalassemia
  Alpha thalassemia
  Adenovirus infection
  Eosinophilic esophagitis
  Ethylmalonic encephalopathy
  Myeloproliferative neoplasm
• UniProt ID: HBS1L_HUMAN
• PDB ID: 5LZW; 5LZX; 5LZY; 5LZZ
• EC Number: 3.6.5.-
• Pfam ID: PF00009 ; PF03144 ; PF03143 ; PF08938
• Sequence:
  MARHRNVRGYNYDEDFEDDDLYGQSVEDDYCISPSTAAQFIYSRRDKPSVEPVEEYDYED
  LKESSNSVSNHQLSGFDQARLYSCLDHMREVLGDAVPDEILIEAVLKNKFDVQKALSGVL
  EQDRVQSLKDKNEATVSTGKIAKGKPVDSQTSRSESEIVPKVAKMTVSGKKQTMGFEVPG
  VSSEENGHSFHTPQKGPPIEDAIASSDVLETASKSANPPHTIQASEEQSSTPAPVKKSGK
  LRQQIDVKAELEKRQGGKQLLNLVVIGHVDAGKSTLMGHMLYLLGNINKRTMHKYEQESK
  KAGKASFAYAWVLDETGEERERGVTMDVGMTKFETTTKVITLMDAPGHKDFIPNMITGAA
  QADVAVLVVDASRGEFEAGFETGGQTREHGLLVRSLGVTQLAVAVNKMDQVNWQQERFQE
  ITGKLGHFLKQAGFKESDVGFIPTSGLSGENLITRSQSSELTKWYKGLCLLEQIDSFKPP
  QRSIDKPFRLCVSDVFKDQGSGFCITGKIEAGYIQTGDRLLAMPPNETCTVKGITLHDEP
  VDWAAAGDHVSLTLVGMDIIKINVGCIFCGPKVPIKACTRFRARILIFNIEIPITKGFPV
  LLHYQTVSEPAVIKRLISVLNKSTGEVTKKKPKFLTKGQNALVELQTQRPIALELYKDFK
  ELGRFMLRYGGSTIAAGVVTEIKE
• Function: GTPase component of the Pelota-HBS1L complex, a complex that recognizes stalled ribosomes and triggers the No-Go Decay (NGD) pathway. The Pelota-HBS1L complex 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.
• Tissue Specificity: Detected in heart, brain, placenta, liver, muscle, kidney and pancreas.
• KEGG Pathway:
  mR. surveillance pathway (hsa03015)
  Legionellosis (hsa05134)
• Reactome Pathway: mRNA decay by 3' to 5' exoribonuclease (R-HSA-429958)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Classic Hodgkin lymphoma	DISV1LU6	Definitive	Genetic Variation	[1]
Hepatitis B virus infection	DISLQ2XY	Definitive	Genetic Variation	[2]
Benign prostatic hyperplasia	DISI3CW2	Strong	Altered Expression	[3]
Beta-thalassemia intermedia	DISYQ0NL	Strong	Genetic Variation	[4]
Cardiac arrest	DIS9DIA4	Strong	Genetic Variation	[5]
Essential thrombocythemia	DISWWK11	Strong	Genetic Variation	[6]
Kidney failure	DISOVQ9P	Strong	Genetic Variation	[7]
Polycythemia vera	DISB5FPO	Strong	Genetic Variation	[8]
Thalassemia	DIS76XZB	Strong	Genetic Variation	[9]
Alpha thalassemia	DIS5XGK0	Disputed	Genetic Variation	[10]
Adenovirus infection	DISUYSBZ	Limited	Altered Expression	[11]
Eosinophilic esophagitis	DISR8WSB	Limited	Genetic Variation	[10]
Ethylmalonic encephalopathy	DISH7SB9	Limited	Genetic Variation	[10]
Myeloproliferative neoplasm	DIS5KAPA	Limited	Genetic Variation	[6]

10 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 HBS1-like protein (HBS1L).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of HBS1-like protein (HBS1L).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of HBS1-like protein (HBS1L).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of HBS1-like protein (HBS1L).	[15]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of HBS1-like protein (HBS1L).	[16]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of HBS1-like protein (HBS1L).	[17]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of HBS1-like protein (HBS1L).	[18]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of HBS1-like protein (HBS1L).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of HBS1-like protein (HBS1L).	[21]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of HBS1-like protein (HBS1L).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of HBS1-like protein (HBS1L).	[20]

References

• [1] Variation at 3p24.1 and 6q23.3 influences the risk of Hodgkin's lymphoma.Nat Commun. 2013;4:2549. doi: 10.1038/ncomms3549.
• [2] A genome-wide association study of chronic hepatitis B identified novel risk locus in a Japanese population.Hum Mol Genet. 2011 Oct 1;20(19):3884-92. doi: 10.1093/hmg/ddr301. Epub 2011 Jul 12.
• [3] Identification of reference genes and miRNAs for RT-qPCR in testosterone propionate-induced benign prostatic hyperplasia in rats.Andrologia. 2018 Feb 14. doi: 10.1111/and.12966. Online ahead of print.
• [4] The XmnI (G)gamma polymorphism influences hemoglobin F synthesis contrary to BCL11A and HBS1L-MYB SNPs in a cohort of 57 beta-thalassemia intermedia patients.Blood Cells Mol Dis. 2010 Aug 15;45(2):124-7. doi: 10.1016/j.bcmd.2010.04.002. Epub 2010 May 15.
• [5] Fine-mapping at three loci known to affect fetal hemoglobin levels explains additional genetic variation.Nat Genet. 2010 Dec;42(12):1049-51. doi: 10.1038/ng.707. Epub 2010 Nov 7.
• [6] MECOM, HBS1L-MYB, THRB-RARB, JAK2, and TERT polymorphisms defining the genetic predisposition to myeloproliferative neoplasms: A study on 939 patients.Am J Hematol. 2018 Jan;93(1):100-106. doi: 10.1002/ajh.24946. Epub 2017 Nov 10.
• [7] Erythropoietin in the general population: reference ranges and clinical, biochemical and genetic correlates.PLoS One. 2015 Apr 27;10(4):e0125215. doi: 10.1371/journal.pone.0125215. eCollection 2015.
• [8] Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms.Nat Commun. 2015 Apr 7;6:6691. doi: 10.1038/ncomms7691.
• [9] Genetic and phenotypic analysis of a rare asymptomatic case of a homozygous Chinese (G)(+)((A))(0)-thalassemia deletion in a Chinese family.Clin Biochem. 2020 Feb;76:11-16. doi: 10.1016/j.clinbiochem.2019.11.003. Epub 2019 Nov 22.
• [10] Variability of hemoglobin F expression in hemoglobin EE disease: hematological and molecular analysis.Blood Cells Mol Dis. 2014 Jun-Aug;53(1-2):11-5. doi: 10.1016/j.bcmd.2014.02.005. Epub 2014 Feb 26.
• [11] Cooperative binding of EF-1A to the E1A enhancer region mediates synergistic effects on E1A transcription during adenovirus infection.J Virol. 1991 Sep;65(9):5084-7. doi: 10.1128/JVI.65.9.5084-5087.1991.
• [12] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [13] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [14] 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.
• [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] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [17] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [18] Curcumin restores corticosteroid function in monocytes exposed to oxidants by maintaining HDAC2. Am J Respir Cell Mol Biol. 2008 Sep;39(3):312-23. doi: 10.1165/rcmb.2008-0012OC. Epub 2008 Apr 17.
• [19] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [20] 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.
• [21] 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.
• [22] Transcriptomic alterations induced by Ochratoxin A in rat and human renal proximal tubular in vitro models and comparison to a rat in vivo model. Arch Toxicol. 2012 Apr;86(4):571-89.