Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2FIEXO)

• DOT Name: E3 ubiquitin-protein ligase RNF220 (RNF220)
• Synonyms: EC 2.3.2.27; RING finger protein 220; RING-type E3 ubiquitin transferase RNF220
• Gene Name: RNF220
• Related Disease:
  Chronic obstructive pulmonary disease
  Leukodystrophy, hypomyelinating, 23, with ataxia, deafness, liver dysfunction, and dilated cardiomyopathy
  Male infertility
• UniProt ID: RN220_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF15926 ; PF13923
• Sequence:
  MDLHRAAFKMENSSYLPNPLASPALMVLASTAEASRDASIPCQQPRPFGVPVSVDKDVHI
  PFTNGSYTFASMYHRQGGVPGTFANRDFPPSLLHLHPQFAPPNLDCTPISMLNHSGVGAF
  RPFASTEDRESYQSAFTPAKRLKNCHDTESPHLRFSDADGKEYDFGTQLPSSSPGSLKVD
  DTGKKIFAVSGLISDREASSSPEDRNDRCKKKAAALFDSQAPICPICQVLLRPSELQEHM
  EQELEQLAQLPSSKNSLLKDAMAPGTPKSLLLSASIKREGESPTASPHSSATDDLHHSDR
  YQTFLRVRANRQTRLNARIGKMKRRKQDEGQREGSCMAEDDAVDIEHENNNRFEEYEWCG
  QKRIRATTLLEGGFRGSGFIMCSGKENPDSDADLDVDGDDTLEYGKPQYTEADVIPCTGE
  EPGEAKEREALRGAVLNGGPPSTRITPEFSKWASDEMPSTSNGESSKQEAMQKTCKNSDI
  EKITEDSAVTTFEALKARVRELERQLSRGDRYKCLICMDSYSMPLTSIQCWHVHCEECWL
  RTLGAKKLCPQCNTITAPGDLRRIYL
• Function: E3 ubiquitin-protein ligase that promotes the ubiquitination and proteasomal degradation of SIN3B. Independently of its E3 ligase activity, acts as a CTNNB1 stabilizer through USP7-mediated deubiquitination of CTNNB1 promoting Wnt signaling. Plays a critical role in the regulation of nuclear lamina.
• Tissue Specificity: Ubiquitously expressed. Abundant in brain and spinal cord, particularly in the cerebellum and cerebral cortex. In fetal tissues expressed in the cerebellum, spinal cord and cortex.
• Reactome Pathway: Antigen processing (R-HSA-983168)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[1]
Leukodystrophy, hypomyelinating, 23, with ataxia, deafness, liver dysfunction, and dilated cardiomyopathy	DIST9VVM	Strong	Autosomal recessive	[2]
Male infertility	DISY3YZZ	Strong	Genetic Variation	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase RNF220 (RNF220).	[4]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of E3 ubiquitin-protein ligase RNF220 (RNF220).	[6]
Selenium	DM25CGV	Approved	Selenium increases the expression of E3 ubiquitin-protein ligase RNF220 (RNF220).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of E3 ubiquitin-protein ligase RNF220 (RNF220).	[5]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of E3 ubiquitin-protein ligase RNF220 (RNF220).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of E3 ubiquitin-protein ligase RNF220 (RNF220).	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of E3 ubiquitin-protein ligase RNF220 (RNF220).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of E3 ubiquitin-protein ligase RNF220 (RNF220).	[8]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of E3 ubiquitin-protein ligase RNF220 (RNF220).	[10]

References

• [1] Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations.Nat Genet. 2019 Mar;51(3):494-505. doi: 10.1038/s41588-018-0342-2. Epub 2019 Feb 25.
• [2] Biallelic mutations in RNF220 cause laminopathies featuring leukodystrophy, ataxia and deafness. Brain. 2021 Nov 29;144(10):3020-3035. doi: 10.1093/brain/awab185.
• [3] A homozygous RNF220 mutation leads to male infertility with small-headed sperm.Gene. 2019 Mar 10;688:13-18. doi: 10.1016/j.gene.2018.11.074. Epub 2018 Nov 27.
• [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] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [6] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [7] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [8] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [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.
• [10] 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.