Details of Drug Off-Target (DOT)

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

• DOT Name: Pre-mRNA-splicing factor SLU7 (SLU7)
• Synonyms: hSlu7
• Gene Name: SLU7
• Related Disease:
  Acute myelogenous leukaemia
  Cardiac failure
  Congestive heart failure
  Estrogen-receptor positive breast cancer
  Haematological malignancy
  Hepatocellular carcinoma
  Myelodysplastic syndrome
  Neoplasm
  Thrombocytosis disease
  Autism spectrum disorder
  Neurodevelopmental disorder
  Pervasive developmental disorder
  Advanced cancer
  Childhood myelodysplastic syndrome
  Retinitis pigmentosa
  Squamous cell carcinoma
• UniProt ID: SLU7_HUMAN
• PDB ID: 5XJC; 6ICZ; 6QDV; 7W5A; 7W5B; 8C6J
• Pfam ID: PF11708
• Sequence:
  MSATVVDAVNAAPLSGSKEMSLEEPKKMTREDWRKKKELEEQRKLGNAPAEVDEEGKDIN
  PHIPQYISSVPWYIDPSKRPTLKHQRPQPEKQKQFSSSGEWYKRGVKENSIITKYRKGAC
  ENCGAMTHKKKDCFERPRRVGAKFTGTNIAPDEHVQPQLMFDYDGKRDRWNGYNPEEHMK
  IVEEYAKVDLAKRTLKAQKLQEELASGKLVEQANSPKHQWGEEEPNSQMEKDHNSEDEDE
  DKYADDIDMPGQNFDSKRRITVRNLRIREDIAKYLRNLDPNSAYYDPKTRAMRENPYANA
  GKNPDEVSYAGDNFVRYTGDTISMAQTQLFAWEAYDKGSEVHLQADPTKLELLYKSFKVK
  KEDFKEQQKESILEKYGGQEHLDAPPAELLLAQTEDYVEYSRHGTVIKGQERAVACSKYE
  EDVKIHNHTHIWGSYWKEGRWGYKCCHSFFKYSYCTGEAGKEIVNSEECIINEITGEESV
  KKPQTLMELHQEKLKEEKKKKKKKKKKHRKSSSDSDDEEKKHEKLKKALNAEEARLLHVK
  ETMQIDERKRPYNSMYETREPTEEEMEAYRMKRQRPDDPMASFLGQ
• Function: Required for pre-mRNA splicing as component of the spliceosome. Participates in the second catalytic step of pre-mRNA splicing, when the free hydroxyl group of exon I attacks the 3'-splice site to generate spliced mRNA and the excised lariat intron. Required for holding exon 1 properly in the spliceosome and for correct AG identification when more than one possible AG exists in 3'-splicing site region. May be involved in the activation of proximal AG. Probably also involved in alternative splicing regulation.
• KEGG Pathway: Spliceosome (hsa03040)
• Reactome Pathway:
  mRNA Splicing - Major Pathway (R-HSA-72163)
  mRNA 3'-end processing (R-HSA-72187)
  RNA Polymerase II Transcription Termination (R-HSA-73856)
  Transport of Mature mRNA derived from an Intron-Containing Transcript (R-HSA-159236)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Genetic Variation	[1]
Cardiac failure	DISDC067	Strong	Altered Expression	[2]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[2]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Biomarker	[3]
Haematological malignancy	DISCDP7W	Strong	Genetic Variation	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
Myelodysplastic syndrome	DISYHNUI	Strong	Genetic Variation	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Thrombocytosis disease	DISNG0P4	Strong	Genetic Variation	[1]
Autism spectrum disorder	DISXK8NV	moderate	Biomarker	[6]
Neurodevelopmental disorder	DIS372XH	moderate	Biomarker	[6]
Pervasive developmental disorder	DIS51975	moderate	Biomarker	[6]
Advanced cancer	DISAT1Z9	Limited	Genetic Variation	[1]
Childhood myelodysplastic syndrome	DISMN80I	Limited	Genetic Variation	[7]
Retinitis pigmentosa	DISCGPY8	Limited	Biomarker	[8]
Squamous cell carcinoma	DISQVIFL	Limited	Biomarker	[9]

8 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 Pre-mRNA-splicing factor SLU7 (SLU7).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Pre-mRNA-splicing factor SLU7 (SLU7).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Pre-mRNA-splicing factor SLU7 (SLU7).	[12]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate decreases the expression of Pre-mRNA-splicing factor SLU7 (SLU7).	[13]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Pre-mRNA-splicing factor SLU7 (SLU7).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Pre-mRNA-splicing factor SLU7 (SLU7).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Pre-mRNA-splicing factor SLU7 (SLU7).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Pre-mRNA-splicing factor SLU7 (SLU7).	[18]

1 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 Pre-mRNA-splicing factor SLU7 (SLU7).	[16]

References

• [1] Mutations in Splicing Factor Genes in Myeloid Malignancies: Significance and Impact on Clinical Features.Cancers (Basel). 2019 Nov 22;11(12):1844. doi: 10.3390/cancers11121844.
• [2] Role of RBM25/LUC7L3 in abnormal cardiac sodium channel splicing regulation in human heart failure.Circulation. 2011 Sep 6;124(10):1124-31. doi: 10.1161/CIRCULATIONAHA.111.044495. Epub 2011 Aug 22.
• [3] Splicing factor ESRP1 controls ER-positive breast cancer by altering metabolic pathways.EMBO Rep. 2019 Feb;20(2):e46078. doi: 10.15252/embr.201846078. Epub 2019 Jan 21.
• [4] Splicing factor gene mutations in hematologic malignancies.Blood. 2017 Mar 9;129(10):1260-1269. doi: 10.1182/blood-2016-10-692400. Epub 2016 Dec 9.
• [5] Splicing regulator SLU7 preserves survival of hepatocellular carcinoma cells and other solid tumors via oncogenic miR-17-92 cluster expression.Oncogene. 2016 Sep 8;35(36):4719-29. doi: 10.1038/onc.2015.517. Epub 2016 Jan 25.
• [6] Essential role of the nuclear isoform of RBFOX1, a candidate gene for autism spectrum disorders, in the brain development.Sci Rep. 2016 Aug 2;6:30805. doi: 10.1038/srep30805.
• [7] Myelodysplastic Syndrome Splicing Factor Mutations Induce R-Loops.Cancer Discov. 2018 Apr;8(4):OF13. doi: 10.1158/2159-8290.CD-RW2018-025. Epub 2018 Feb 9.
• [8] Autosomal-dominant retinitis pigmentosa caused by a mutation in SNRNP200, a gene required for unwinding of U4/U6 snRNAs.Am J Hum Genet. 2009 Nov;85(5):617-27. doi: 10.1016/j.ajhg.2009.09.020. Epub 2009 Oct 29.
• [9] Splicing factor derived circular RNA circUHRF1 accelerates oral squamous cell carcinoma tumorigenesis via feedback loop.Cell Death Differ. 2020 Mar;27(3):919-933. doi: 10.1038/s41418-019-0423-5. Epub 2019 Sep 30.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Gene expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins. Physiol Genomics. 2004 Jan 15;16(2):204-11.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [16] 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.
• [17] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.