Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNAXM6D)

• DOT Name: E3 ubiquitin-protein ligase RNF6 (RNF6)
• Synonyms: EC 2.3.2.27
• Gene Name: RNF6
• Related Disease: Esophageal cancer
• UniProt ID: RNF6_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF13639
• Sequence:
  MNQSRSRSDGGSEETLPQDHNHHENERRWQQERLHREEAYYQFINELNDEDYRLMRDHNL
  LGTPGEITSEELQQRLDGVKEQLASQPDLRDGTNYRDSEVPRESSHEDSLLEWLNTFRRT
  GNATRSGQNGNQTWRAVSRTNPNNGEFRFSLEIHVNHENRGFEIHGEDYTDIPLSDSNRD
  HTANRQQRSTSPVARRTRSQTSVNFNGSSSNIPRTRLASRGQNPAEGSFSTLGRLRNGIG
  GAAGIPRANASRTNFSSHTNQSGGSELRQREGQRFGAAHVWENGARSNVTVRNTNQRLEP
  IRLRSTSNSRSRSPIQRQSGTVYHNSQRESRPVQQTTRRSVRRRGRTRVFLEQDRERERR
  GTAYTPFSNSRLVSRITVEEGEESSRSSTAVRRHPTITLDLQVRRIRPGENRDRDSIANR
  TRSRVGLAENTVTIESNSGGFRRTISRLERSGIRTYVSTITVPLRRISENELVEPSSVAL
  RSILRQIMTGFGELSSLMEADSESELQRNGQHLPDMHSELSNLGTDNNRSQHREGSSQDR
  QAQGDSTEMHGENETTQPHTRNSDSRGGRQLRNPNNLVETGTLPILRLAHFFLLNESDDD
  DRIRGLTKEQIDNLSTRHYEHNSIDSELGKICSVCISDYVTGNKLRQLPCMHEFHIHCID
  RWLSENCTCPICRQPVLGSNIANNG
• Function: E3 ubiquitin-protein ligase mediating 'Lys-48'-linked polyubiquitination of LIMK1 and its subsequent targeting to the proteasome for degradation. Negatively regulates axonal outgrowth through regulation of the LIMK1 turnover. Mediates 'Lys-6' and 'Lys-27'-linked polyubiquitination of AR/androgen receptor thereby modulating its transcriptional activity. May also bind DNA and function as a transcriptional regulator. Mediates polyubiquitination of QKI in macrophages, leading to its degradation.
• Tissue Specificity: Weakly expressed in peripheral blood, spleen, prostate, testis and ovary . According to a report, it is preferentially expressed in testis and ovary and hardly detected in other tissues .
• Reactome Pathway: Antigen processing (R-HSA-983168)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Esophageal cancer	DISGB2VN	No Known	Unknown	[1]

7 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 E3 ubiquitin-protein ligase RNF6 (RNF6).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of E3 ubiquitin-protein ligase RNF6 (RNF6).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of E3 ubiquitin-protein ligase RNF6 (RNF6).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of E3 ubiquitin-protein ligase RNF6 (RNF6).	[5]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of E3 ubiquitin-protein ligase RNF6 (RNF6).	[6]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of E3 ubiquitin-protein ligase RNF6 (RNF6).	[7]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of E3 ubiquitin-protein ligase RNF6 (RNF6).	[8]

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 increases the methylation of E3 ubiquitin-protein ligase RNF6 (RNF6).	[9]

References

• [1] The spectrum of genetic variants in hereditary pancreatic cancer includes Fanconi anemia genes. Fam Cancer. 2018 Apr;17(2):235-245. doi: 10.1007/s10689-017-0019-5.
• [2] 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.
• [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] 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] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [6] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [7] Integrated analysis of rifampicin-induced microRNA and gene expression changes in human hepatocytes. Drug Metab Pharmacokinet. 2014;29(4):333-40.
• [8] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [9] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.