Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6AZXX8)

• DOT Name: E3 ubiquitin-protein ligase RNF168 (RNF168)
• Synonyms: hRNF168; EC 2.3.2.27; RING finger protein 168; RING-type E3 ubiquitin transferase RNF168
• Gene Name: RNF168
• Related Disease:
  Adult glioblastoma
  Glioblastoma multiforme
  RIDDLE syndrome
  Ataxia-telangiectasia
  Dengue
  Esophageal cancer
  Estrogen-receptor positive breast cancer
  Fanconi anemia complementation group A
  Fanconi's anemia
  Neoplasm
  Advanced cancer
  Immunodeficiency
• UniProt ID: RN168_HUMAN
• PDB ID: 3L11; 4GB0; 5XIS; 5XIT; 5XIU; 5YDK
• EC Number: 2.3.2.27
• Pfam ID: PF00097
• Sequence:
  MALPKDAIPSLSECQCGICMEILVEPVTLPCNHTLCKPCFQSTVEKASLCCPFCRRRVSS
  WTRYHTRRNSLVNVELWTIIQKHYPRECKLRASGQESEEVADDYQPVRLLSKPGELRREY
  EEEISKVAAERRASEEEENKASEEYIQRLLAEEEEEEKRQAEKRRRAMEEQLKSDEELAR
  KLSIDINNFCEGSISASPLNSRKSDPVTPKSEKKSKNKQRNTGDIQKYLTPKSQFGSASH
  SEAVQEVRKDSVSKDIDSSDRKSPTGQDTEIEDMPTLSPQISLGVGEQGADSSIESPMPW
  LCACGAEWYHEGNVKTRPSNHGKELCVLSHERPKTRVPYSKETAVMPCGRTESGCAPTSG
  VTQTNGNNTGETENEESCLLISKEISKRKNQESSFEAVKDPCFSAKRRKVSPESSPDQEE
  TEINFTQKLIDLEHLLFERHKQEEQDRLLALQLQKEVDKEQMVPNRQKGSPDEYHLRATS
  SPPDKVLNGQRKNPKDGNFKRQTHTKHPTPERGSRDKNRQVSLKMQLKQSVNRRKMPNST
  RDHCKVSKSAHSLQPSISQKSVFQMFQRCTK
• Function: E3 ubiquitin-protein ligase required for accumulation of repair proteins to sites of DNA damage. Acts with UBE2N/UBC13 to amplify the RNF8-dependent histone ubiquitination. Recruited to sites of DNA damage at double-strand breaks (DSBs) by binding to ubiquitinated histone H2A and H2AX and amplifies the RNF8-dependent H2A ubiquitination, promoting the formation of 'Lys-63'-linked ubiquitin conjugates. This leads to concentrate ubiquitinated histones H2A and H2AX at DNA lesions to the threshold required for recruitment of TP53BP1 and BRCA1. Also recruited at DNA interstrand cross-links (ICLs) sites and promotes accumulation of '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. Also involved in class switch recombination in immune system, via its role in regulation of DSBs repair. Following DNA damage, promotes the ubiquitination and degradation of JMJD2A/KDM4A in collaboration with RNF8, leading to unmask H4K20me2 mark and promote the recruitment of TP53BP1 at DNA damage sites. Not able to initiate 'Lys-63'-linked ubiquitination in vitro; possibly due to partial occlusion of the UBE2N/UBC13-binding region. Catalyzes monoubiquitination of 'Lys-13' and 'Lys-15' of nucleosomal histone H2A (H2AK13Ub and H2AK15Ub, respectively).
• Reactome Pathway:
  Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks (R-HSA-5693565)
  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)
  SUMOylation of DNA damage response and repair proteins (R-HSA-3108214)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Definitive	Altered Expression	[1]
Glioblastoma multiforme	DISK8246	Definitive	Altered Expression	[1]
RIDDLE syndrome	DISZ67F2	Definitive	Autosomal recessive	[2]
Ataxia-telangiectasia	DISP3EVR	Strong	Genetic Variation	[3]
Dengue	DISKH221	Strong	Biomarker	[4]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[5]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Biomarker	[6]
Fanconi anemia complementation group A	DIS8PZLI	Strong	Biomarker	[7]
Fanconi's anemia	DISGW6Q8	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[8]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[9]
Immunodeficiency	DIS093I0	Limited	Genetic Variation	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of E3 ubiquitin-protein ligase RNF168 (RNF168).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of E3 ubiquitin-protein ligase RNF168 (RNF168).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase RNF168 (RNF168).	[13]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of E3 ubiquitin-protein ligase RNF168 (RNF168).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of E3 ubiquitin-protein ligase RNF168 (RNF168).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of E3 ubiquitin-protein ligase RNF168 (RNF168).	[15]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of E3 ubiquitin-protein ligase RNF168 (RNF168).	[17]

References

• [1] A PRMT5-RNF168-SMURF2 Axis Controls H2AX Proteostasis.Cell Rep. 2019 Sep 17;28(12):3199-3211.e5. doi: 10.1016/j.celrep.2019.08.031.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Ataxia telangiectasia: more variation at clinical and cellular levels.Clin Genet. 2015 Mar;87(3):199-208. doi: 10.1111/cge.12453. Epub 2014 Sep 8.
• [4] A model framework to estimate impact and cost of genetics-based sterile insect methods for dengue vector control.PLoS One. 2011;6(10):e25384. doi: 10.1371/journal.pone.0025384. Epub 2011 Oct 5.
• [5] RNF168 facilitates proliferation and invasion of esophageal carcinoma, possibly via stabilizing STAT1.J Cell Mol Med. 2019 Feb;23(2):1553-1561. doi: 10.1111/jcmm.14063. Epub 2018 Dec 3.
• [6] RNF168 facilitates oestrogen receptor transcription and drives breast cancer proliferation.J Cell Mol Med. 2018 Sep;22(9):4161-4170. doi: 10.1111/jcmm.13694. Epub 2018 Jul 5.
• [7] A ubiquitin-binding protein, FAAP20, links RNF8-mediated ubiquitination to the Fanconi anemia DNA repair network.Mol Cell. 2012 Jul 13;47(1):61-75. doi: 10.1016/j.molcel.2012.05.026. Epub 2012 Jun 14.
• [8] The mTOR-S6K pathway links growth signalling to DNA damage response by targeting RNF168.Nat Cell Biol. 2018 Mar;20(3):320-331. doi: 10.1038/s41556-017-0033-8. Epub 2018 Feb 5.
• [9] BRCA1 Haploinsufficiency Is Masked by RNF168-Mediated Chromatin Ubiquitylation.Mol Cell. 2019 Mar 21;73(6):1267-1281.e7. doi: 10.1016/j.molcel.2018.12.010. Epub 2019 Jan 28.
• [10] The 3q29 microdeletion syndrome: report of three new unrelated patients and in silico "RNA binding" analysis of the 3q29 region.Am J Med Genet A. 2011 Jul;155A(7):1654-60. doi: 10.1002/ajmg.a.34080. Epub 2011 May 27.
• [11] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [12] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [13] 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.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [16] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [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.