Details of Drug Off-Target (DOT)

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

• DOT Name: Lariat debranching enzyme (DBR1)
• Synonyms: EC 3.1.4.-
• Gene Name: DBR1
• Related Disease:
  Amyotrophic lateral sclerosis-parkinsonism-dementia complex
  Breast cancer
  Breast carcinoma
  Encephalitis, acute, infection (viral)-induced, susceptibility to, 11
  Hairy cell leukaemia
  Hemolytic-uremic syndrome
  Herpes simplex infection
  Encephalitis
  Advanced cancer
  Amyotrophic lateral sclerosis
  Rheumatoid arthritis
• UniProt ID: DBR1_HUMAN
• EC Number: 3.1.4.-
• Pfam ID: PF05011 ; PF00149
• Sequence:
  MRVAVAGCCHGELDKIYETLALAERRGPGPVDLLLCCGDFQAVRNEADLRCMAVPPKYRH
  MQTFYRYYSGEKKAPVLTLFIGGNHEASNHLQELPYGGWVAPNIYYLGLAGVVKYRGVRI
  GGISGIFKSHDYRKGHFECPPYNSSTIRSIYHVRNIEVYKLKQLKQPIDIFLSHDWPRSI
  YHYGNKKQLLKTKSFFRQEVENNTLGSPAASELLEHLKPTYWFSAHLHVKFAALMQHQAK
  DKGQTARATKFLALDKCLPHRDFLQILEIEHDPSAPDYLEYDIEWLTILRATDDLINVTG
  RLWNMPENNGLHARWDYSATEEGMKEVLEKLNHDLKVPCNFSVTAACYDPSKPQTQMQLI
  HRINPQTTEFCAQLGIIDINVRLQKSKEEHHVCGEYEEQDDVESNDSGEDQSEYNTDTSA
  LSSINPDEIMLDEEEDEDSIVSAHSGMNTPSVEPSDQASEFSASFSDVRILPGSMIVSSD
  DTVDSTIDREGKPGGTVESGNGEDLTKVPLKRLSDEHEPEQRKKIKRRNQAIYAAVDDDD
  DDAA
• Function: Cleaves the 2'-5' phosphodiester linkage at the branch point of excised lariat intron RNA and converts them into linear molecules that can be subsequently degraded, thereby facilitating ribonucleotide turnover. Linked to its role in pre-mRNA processing mechanism, may also participate in retrovirus replication via an RNA lariat intermediate in cDNA synthesis and have an antiviral cell-intrinsic defense function in the brainstem.
• Tissue Specificity: Ubiquitously expressed, strongest expression in the spinal cord and brainstem.

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Amyotrophic lateral sclerosis-parkinsonism-dementia complex	DISTHQI1	Strong	Therapeutic	[1]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[2]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[2]
Encephalitis, acute, infection (viral)-induced, susceptibility to, 11	DIS1X3ZV	Strong	Autosomal recessive	[3]
Hairy cell leukaemia	DISTD2E5	Strong	Biomarker	[4]
Hemolytic-uremic syndrome	DISSCBGW	Strong	Biomarker	[4]
Herpes simplex infection	DISL1SAV	Strong	Genetic Variation	[5]
Encephalitis	DISLD1RL	moderate	Biomarker	[6]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[7]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Altered Expression	[1]
Rheumatoid arthritis	DISTSB4J	Limited	Genetic Variation	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Lariat debranching enzyme (DBR1).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Lariat debranching enzyme (DBR1).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Lariat debranching enzyme (DBR1).	[11]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Lariat debranching enzyme (DBR1).	[12]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Lariat debranching enzyme (DBR1).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Lariat debranching enzyme (DBR1).	[14]

References

• [1] Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models.Nat Genet. 2012 Dec;44(12):1302-9. doi: 10.1038/ng.2434. Epub 2012 Oct 28.
• [2] HLA-DBR 1 alleles and the susceptibility of Iranian patients with breast cancer.Pathol Oncol Res. 2001;7(1):39-41. doi: 10.1007/BF03032603.
• [3] Structural basis of lariat RNA recognition by the intron debranching enzyme Dbr1. Nucleic Acids Res. 2014;42(16):10845-55. doi: 10.1093/nar/gku725. Epub 2014 Aug 14.
• [4] Class II human leucocyte antigen DRB1*11 in hairy cell leukaemia patients with and without haemolytic uraemic syndrome.Br J Haematol. 2014 Sep;166(5):729-38. doi: 10.1111/bjh.12956. Epub 2014 Jun 13.
• [5] Inborn Errors of RNA Lariat Metabolism in Humans with Brainstem Viral Infection.Cell. 2018 Feb 22;172(5):952-965.e18. doi: 10.1016/j.cell.2018.02.019.
• [6] Human SNORA31 variations impair cortical neuron-intrinsic immunity to HSV-1 and underlie herpes simplex encephalitis.Nat Med. 2019 Dec;25(12):1873-1884. doi: 10.1038/s41591-019-0672-3. Epub 2019 Dec 5.
• [7] Human DBR1 modulates the recycling of snRNPs to affect alternative RNA splicing and contributes to the suppression of cancer development.Oncogene. 2017 Sep 21;36(38):5382-5391. doi: 10.1038/onc.2017.150. Epub 2017 May 15.
• [8] Protective effect of HLA-DRB1*13 alleles during specific phases in the development of ACPA-positive RA.Ann Rheum Dis. 2016 Oct;75(10):1891-8. doi: 10.1136/annrheumdis-2015-207802. Epub 2015 Dec 29.
• [9] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [12] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [13] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.