General Information of Drug Off-Target (DOT) (ID: OTRR43PZ)

DOT Name E3 ubiquitin-protein ligase RNF8 (RNF8)
Synonyms hRNF8; EC 2.3.2.27; RING finger protein 8; RING-type E3 ubiquitin transferase RNF8
Gene Name RNF8
Related Disease
Autism ( )
Bladder cancer ( )
Esophageal squamous cell carcinoma ( )
Medulloblastoma ( )
Non-small-cell lung cancer ( )
Ovarian cancer ( )
Promyelocytic leukaemia ( )
Triple negative breast cancer ( )
Urinary bladder cancer ( )
Urinary bladder neoplasm ( )
Neuroblastoma ( )
Advanced cancer ( )
Breast cancer ( )
Breast carcinoma ( )
Fanconi anemia complementation group A ( )
Fanconi's anemia ( )
Neoplasm ( )
UniProt ID
RNF8_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
2CSW; 2PIE; 4AYC; 4ORH; 4WHV
EC Number
2.3.2.27
Pfam ID
PF00498 ; PF13920
Sequence
MGEPGFFVTGDRAGGRSWCLRRVGMSAGWLLLEDGCEVTVGRGFGVTYQLVSKICPLMIS
RNHCVLKQNPEGQWTIMDNKSLNGVWLNRARLEPLRVYSIHQGDYIQLGVPLENKENAEY
EYEVTEEDWETIYPCLSPKNDQMIEKNKELRTKRKFSLDELAGPGAEGPSNLKSKINKVS
CESGQPVKSQGKGEVASTPSDNLDPKLTALEPSKTTGAPIYPGFPKVTEVHHEQKASNSS
ASQRSLQMFKVTMSRILRLKIQMQEKHEAVMNVKKQTQKGNSKKVVQMEQELQDLQSQLC
AEQAQQQARVEQLEKTFQEEEQHLQGLEIAQGEKDLKQQLAQALQEHWALMEELNRSKKD
FEAIIQAKNKELEQTKEEKEKMQAQKEEVLSHMNDVLENELQCIICSEYFIEAVTLNCAH
SFCSYCINEWMKRKIECPICRKDIKSKTYSLVLDNCINKMVNNLSSEVKERRIVLIRERK
AKRLF
Function
E3 ubiquitin-protein ligase that plays a key role in DNA damage signaling via 2 distinct roles: by mediating the 'Lys-63'-linked ubiquitination of histones H2A and H2AX and promoting the recruitment of DNA repair proteins at double-strand breaks (DSBs) sites, and by catalyzing 'Lys-48'-linked ubiquitination to remove target proteins from DNA damage sites. Following DNA DSBs, it is recruited to the sites of damage by ATM-phosphorylated MDC1 and catalyzes the 'Lys-63'-linked ubiquitination of histones H2A and H2AX, thereby promoting the formation of TP53BP1 and BRCA1 ionizing radiation-induced foci (IRIF). Also controls the recruitment of UIMC1-BRCC3 (RAP80-BRCC36) and PAXIP1/PTIP to DNA damage sites. Also recruited at DNA interstrand cross-links (ICLs) sites and catalyzes 'Lys-63'-linked ubiquitination of histones H2A and H2AX, leading to recruitment of FAAP20/C1orf86 and Fanconi anemia (FA) complex, followed by interstrand cross-link repair. H2A ubiquitination also mediates the ATM-dependent transcriptional silencing at regions flanking DSBs in cis, a mechanism to avoid collision between transcription and repair intermediates. Promotes the formation of 'Lys-63'-linked polyubiquitin chains via interactions with the specific ubiquitin-conjugating UBE2N/UBC13 and ubiquitinates non-histone substrates such as PCNA. Substrates that are polyubiquitinated at 'Lys-63' are usually not targeted for degradation. Also catalyzes the formation of 'Lys-48'-linked polyubiquitin chains via interaction with the ubiquitin-conjugating UBE2L6/UBCH8, leading to degradation of substrate proteins such as CHEK2, JMJD2A/KDM4A and KU80/XRCC5: it is still unclear how the preference toward 'Lys-48'- versus 'Lys-63'-linked ubiquitination is regulated but it could be due to RNF8 ability to interact with specific E2 specific ligases. For instance, interaction with phosphorylated HERC2 promotes the association between RNF8 and UBE2N/UBC13 and favors the specific formation of 'Lys-63'-linked ubiquitin chains. Promotes non-homologous end joining (NHEJ) by promoting the 'Lys-48'-linked ubiquitination and degradation the of KU80/XRCC5. Following DNA damage, mediates the ubiquitination and degradation of JMJD2A/KDM4A in collaboration with RNF168, leading to unmask H4K20me2 mark and promote the recruitment of TP53BP1 at DNA damage sites. Following DNA damage, mediates the ubiquitination and degradation of POLD4/p12, a subunit of DNA polymerase delta. In the absence of POLD4, DNA polymerase delta complex exhibits higher proofreading activity. In addition to its function in damage signaling, also plays a role in higher-order chromatin structure by mediating extensive chromatin decondensation. Involved in the activation of ATM by promoting histone H2B ubiquitination, which indirectly triggers histone H4 'Lys-16' acetylation (H4K16ac), establishing a chromatin environment that promotes efficient activation of ATM kinase. Required in the testis, where it plays a role in the replacement of histones during spermatogenesis. At uncapped telomeres, promotes the joining of deprotected chromosome ends by inducing H2A ubiquitination and TP53BP1 recruitment, suggesting that it may enhance cancer development by aggravating telomere-induced genome instability in case of telomeric crisis. Promotes the assembly of RAD51 at DNA DSBs in the absence of BRCA1 and TP53BP1 Also involved in class switch recombination in immune system, via its role in regulation of DSBs repair. May be required for proper exit from mitosis after spindle checkpoint activation and may regulate cytokinesis. May play a role in the regulation of RXRA-mediated transcriptional activity. Not involved in RXRA ubiquitination by UBE2E2.
Tissue Specificity Ubiquitous. In fetal tissues, highest expression in brain, thymus and liver. In adult tissues, highest levels in brain and testis, lowest levels in peripheral blood cells.
Reactome Pathway
Nonhomologous End-Joining (NHEJ) (R-HSA-5693571 )
Processing of DNA double-strand break ends (R-HSA-5693607 )
G2/M DNA damage checkpoint (R-HSA-69473 )
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks (R-HSA-5693565 )

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Autism DISV4V1Z Strong Biomarker [1]
Bladder cancer DISUHNM0 Strong Biomarker [2]
Esophageal squamous cell carcinoma DIS5N2GV Strong Biomarker [3]
Medulloblastoma DISZD2ZL Strong Biomarker [4]
Non-small-cell lung cancer DIS5Y6R9 Strong Biomarker [5]
Ovarian cancer DISZJHAP Strong Altered Expression [6]
Promyelocytic leukaemia DISYGG13 Strong Genetic Variation [7]
Triple negative breast cancer DISAMG6N Strong Posttranslational Modification [8]
Urinary bladder cancer DISDV4T7 Strong Biomarker [2]
Urinary bladder neoplasm DIS7HACE Strong Biomarker [2]
Neuroblastoma DISVZBI4 moderate Biomarker [9]
Advanced cancer DISAT1Z9 Limited Biomarker [10]
Breast cancer DIS7DPX1 Limited Biomarker [11]
Breast carcinoma DIS2UE88 Limited Biomarker [11]
Fanconi anemia complementation group A DIS8PZLI Limited Biomarker [12]
Fanconi's anemia DISGW6Q8 Limited Biomarker [12]
Neoplasm DISZKGEW Limited Biomarker [10]
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⏷ Show the Full List of 17 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
4 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate decreases the expression of E3 ubiquitin-protein ligase RNF8 (RNF8). [13]
Temozolomide DMKECZD Approved Temozolomide increases the expression of E3 ubiquitin-protein ligase RNF8 (RNF8). [15]
Amiodarone DMUTEX3 Phase 2/3 Trial Amiodarone increases the expression of E3 ubiquitin-protein ligase RNF8 (RNF8). [16]
3R14S-OCHRATOXIN A DM2KEW6 Investigative 3R14S-OCHRATOXIN A decreases the expression of E3 ubiquitin-protein ligase RNF8 (RNF8). [18]
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3 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 RNF8 (RNF8). [14]
PMID28870136-Compound-52 DMFDERP Patented PMID28870136-Compound-52 decreases the phosphorylation of E3 ubiquitin-protein ligase RNF8 (RNF8). [17]
Coumarin DM0N8ZM Investigative Coumarin increases the phosphorylation of E3 ubiquitin-protein ligase RNF8 (RNF8). [17]
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References

1 Identifying autism loci and genes by tracing recent shared ancestry.Science. 2008 Jul 11;321(5886):218-23. doi: 10.1126/science.1157657.
2 Adenovirus-mediated downregulation of the ubiquitin ligase RNF8 sensitizes bladder cancer to radiotherapy.Oncotarget. 2016 Feb 23;7(8):8956-67. doi: 10.18632/oncotarget.6909.
3 Corilagin Inhibits Esophageal Squamous Cell Carcinoma by Inducing DNA Damage and Down-Regulation of RNF8.Anticancer Agents Med Chem. 2019;19(8):1021-1028. doi: 10.2174/1871520619666190307120811.
4 Silencing of E3 Ubiquitin Ligase RNF8 Enhances Ionizing Radiation Sensitivity of Medulloblastoma Cells by Promoting the Deubiquitination of PCNA.Oncol Res. 2018 Oct 17;26(9):1365-1373. doi: 10.3727/096504018X15154085345907. Epub 2018 Jan 10.
5 RNAi silencing targeting RNF8 enhances radiosensitivity of a non-small cell lung cancer cell line A549.Int J Radiat Biol. 2013 Sep;89(9):708-15. doi: 10.3109/09553002.2013.792964. Epub 2013 May 15.
6 miR-214-mediated downregulation of RNF8 induces chromosomal instability in ovarian cancer cells.Cell Cycle. 2014;13(22):3519-28. doi: 10.4161/15384101.2014.958413.
7 RNF8 is responsible for ATRA resistance in variant acute promyelocytic leukemia with GTF2I/RARA fusion, and inhibition of the ubiquitin-proteasome pathway contributes to the reversion of ATRA resistance.Cancer Cell Int. 2019 Apr 4;19:84. doi: 10.1186/s12935-019-0803-4. eCollection 2019.
8 Aberrant DNA methylation status of DNA repair genes in breast cancer treated with neoadjuvant chemotherapy.Genes Cells. 2013 Dec;18(12):1120-30. doi: 10.1111/gtc.12100. Epub 2013 Oct 28.
9 Isolation, tissue expression, and chromosomal assignment of a novel human gene which encodes a protein with RING finger motif.J Hum Genet. 1998;43(4):272-4. doi: 10.1007/s100380050088.
10 The p97-Ataxin 3 complex regulates homeostasis of the DNA damage response E3 ubiquitin ligase RNF8.EMBO J. 2019 Oct 4;38(21):e102361. doi: 10.15252/embj.2019102361. Epub 2019 Oct 15.
11 Bioinformatic Identification of miR-622 Key Target Genes and Experimental Validation of the miR-622-RNF8 Axis in Breast Cancer.Front Oncol. 2019 Oct 23;9:1114. doi: 10.3389/fonc.2019.01114. eCollection 2019.
12 Coordination of the recruitment of the FANCD2 and PALB2 Fanconi anemia proteins by an ubiquitin signaling network.Chromosoma. 2017 Jun;126(3):417-430. doi: 10.1007/s00412-016-0602-9. Epub 2016 Jun 8.
13 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
14 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.
15 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.
16 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.
17 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.
18 Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.