Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLS6875)

• DOT Name: E3 ubiquitin-protein ligase RNF169 (RNF169)
• Synonyms: EC 2.3.2.27; RING finger protein 169; RING-type E3 ubiquitin transferase RNF169
• Gene Name: RNF169
• Related Disease:
  Breast cancer
  Breast carcinoma
• UniProt ID: RN169_HUMAN
• PDB ID: 5GG4; 5VEY
• EC Number: 2.3.2.27
• Pfam ID: PF13920
• Sequence:
  MAAAGPSTRASSAAAAAALSRRGRRGRCDETAAAKTGAPGPASGPSLLVLSPPLLQPPLP
  PRPEESGCAGCLEPPGEAAALPCGHSLCRGCAQRAADAAGPGCPRCRARGPGWARRRARD
  DGQADSEVLGECARRSQPERCRPRRDGGAAAAGPRPEQEPRAAPAEPDFIFRAPIKLSKP
  GELREEYESLRKLREEKLQEEKPSEDQIHKLLPEDTETGKRKMDEQKKRDEPLVLKTNLE
  RCPARLSDSENEEPSRGQMTQTHRSAFVSKNNSYSLAFLAGKLNSKVERSQSCSDTAQER
  AKSRVRAVPGNKAKVTTMTPASNPIIGVLLSTQNNRCVSAPDLTIEKRLPFSSLSSLASL
  HKPERSVSPESNDSISEELNHFKPIVCSPCTPPKRLPDGRVLSPLIIKSTPRNLNRSLQK
  QTSYEASPRILKKWEQIFQERQIKKTLSKATLTSLAPEMGEELLGSEGIHSSKEKPLVAV
  NTRLSGGQVLSEYTGPTSADLDHFPSVSQTKAEQDSDNKSSTEIPLETCCSSELKGGGSG
  TSLEREQFEGLGSTPDAKLDKTCISRAMKITTVNSVLPQNSVLGGVLKTKQQLKTLNHFD
  LTNGVLVESLSEEPLPSLRRGRKRHCKTKHLEQNGSLKKLRQTSGEVGLAPTDPVLREME
  QKLQQEEEDRQLALQLQRMFDNERRTVSRRKGSVDQYLLRSSNMAGAK
• Function: Probable E3 ubiquitin-protein ligase that acts as a regulator of double-strand breaks (DSBs) repair following DNA damage. Functions in a non-canonical fashion to harness RNF168-mediated protein recruitment to DSB-containing chromatin, thereby contributing to regulation of DSB repair pathway utilization. Once recruited to DSB repair sites by recognizing and binding ubiquitin catalyzed by RNF168, competes with TP53BP1 and BRCA1 for association with RNF168-modified chromatin, thereby favouring homologous recombination repair (HRR) and single-strand annealing (SSA) instead of non-homologous end joining (NHEJ) mediated by TP53BP1. E3 ubiquitin-protein ligase activity is not required for regulation of DSBs repair.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of E3 ubiquitin-protein ligase RNF169 (RNF169).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase RNF169 (RNF169).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of E3 ubiquitin-protein ligase RNF169 (RNF169).	[4]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of E3 ubiquitin-protein ligase RNF169 (RNF169).	[6]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of E3 ubiquitin-protein ligase RNF169 (RNF169).	[8]

3 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 RNF169 (RNF169).	[5]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of E3 ubiquitin-protein ligase RNF169 (RNF169).	[7]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of E3 ubiquitin-protein ligase RNF169 (RNF169).	[9]

References

• [1] Dual-utility NLS drives RNF169-dependent DNA damage responses.Proc Natl Acad Sci U S A. 2017 Apr 4;114(14):E2872-E2881. doi: 10.1073/pnas.1616602114. Epub 2017 Mar 21.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] 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.
• [4] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [5] 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.
• [6] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [7] 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.
• [8] 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.
• [9] 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.