Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY6HNI7)

• DOT Name: G-rich sequence factor 1 (GRSF1)
• Synonyms: GRSF-1
• Gene Name: GRSF1
• Related Disease: Influenza
• UniProt ID: GRSF1_HUMAN
• PDB ID: 2LMI; 4QU6; 4QU7
• Pfam ID: PF00076
• Sequence:
  MAGTRWVLGALLRGCGCNCSSCRRTGAACLPFYSAAGSIPSGVSGRRRLLLLLGAAAAAA
  SQTRGLQTGPVPPGRLAGPPAVATSAAAAAAASYSALRASLLPQSLAAAAAVPTRSYSQE
  SKTTYLEDLPPPPEYELAPSKLEEEVDDVFLIRAQGLPWSCTMEDVLNFFSDCRIRNGEN
  GIHFLLNRDGKRRGDALIEMESEQDVQKALEKHRMYMGQRYVEVYEINNEDVDALMKSLQ
  VKSSPVVNDGVVRLRGLPYSCNEKDIVDFFAGLNIVDITFVMDYRGRRKTGEAYVQFEEP
  EMANQALLKHREEIGNRYIEIFPSRRNEVRTHVGSYKGKKIASFPTAKYITEPEMVFEEH
  EVNEDIQPMTAFESEKEIELPKEVPEKLPEAADFGTTSSLHFVHMRGLPFQANAQDIINF
  FAPLKPVRITMEYSSSGKATGEADVHFETHEDAVAAMLKDRSHVHHRYIELFLNSCPKGK
• Function: Regulator of post-transcriptional mitochondrial gene expression, required for assembly of the mitochondrial ribosome and for recruitment of mRNA and lncRNA. Binds RNAs containing the 14 base G-rich element. Preferentially binds RNAs transcribed from three contiguous genes on the light strand of mtDNA, the ND6 mRNA, and the long non-coding RNAs for MT-CYB and MT-ND5, each of which contains multiple consensus binding sequences. Involved in the degradosome-mediated decay of non-coding mitochondrial transcripts (MT-ncRNA) and tRNA-like molecules. Acts by unwinding G-quadruplex RNA structures in MT-ncRNA, thus facilitating their degradation by the degradosome. G-quadruplexes (G4) are non-canonical 4 stranded structures formed by transcripts from the light strand of mtDNA.
• Reactome Pathway:
  Mitochondrial RNA degradation (R-HSA-9836573)
  Viral mRNA Translation (R-HSA-192823)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Influenza	DIS3PNU3	Strong	Biomarker	[1]

7 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 G-rich sequence factor 1 (GRSF1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of G-rich sequence factor 1 (GRSF1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of G-rich sequence factor 1 (GRSF1).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of G-rich sequence factor 1 (GRSF1).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of G-rich sequence factor 1 (GRSF1).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of G-rich sequence factor 1 (GRSF1).	[9]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of G-rich sequence factor 1 (GRSF1).	[10]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of G-rich sequence factor 1 (GRSF1).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of G-rich sequence factor 1 (GRSF1).	[8]

References

• [1] Regulation of eukaryotic protein synthesis: selective influenza viral mRNA translation is mediated by the cellular RNA-binding protein GRSF-1.Proc Natl Acad Sci U S A. 1999 Jun 8;96(12):6694-9. doi: 10.1073/pnas.96.12.6694.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] 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.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 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.
• [7] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [8] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [9] 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.
• [10] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.