Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFGHB1E)

• DOT Name: SR-related and CTD-associated factor 4 (SCAF4)
• Synonyms: CTD-binding SR-like protein RA4; Splicing factor, arginine/serine-rich 15
• Gene Name: SCAF4
• Related Disease:
  Complex neurodevelopmental disorder
  Diabetic kidney disease
• UniProt ID: SCAF4_HUMAN
• PDB ID: 6XKB
• Pfam ID: PF04818 ; PF00076
• Sequence:
  MDAVNAFNQELFSLMDMKPPISRAKMILITKAAIKAIKLYKHVVQIVEKFIKKCKPEYKV
  PGLYVIDSIVRQSRHQFGTDKDVFGPRFSKNITATFQYLYLCPSEDKSKIVRVLNLWQKN
  GVFKIEIIQPLLDMAAGTSNAAPVAENVTNNEGSPPPPVKVSSEPPTQATPNSVPAVPQL
  PSSDAFAAVAQLFQTTQGQQLQQILQTFQQPPKPQSPALDNAVMAQVQAITAQLKTTPTQ
  PSEQKAAFPPPEQKTAFDKKLLDRFDYDDEPEAVEESKKEDTTAVTTTAPAAAVPPAPTA
  TVPAAAAPAAASPPPPQAPFGFPGDGMQQPAYTQHQNMDQFQPRMMGIQQDPMHHQVPLP
  PNGQMPGFGLLPTPPFPPMAQPVIPPTPPVQQPFQASFQAQNEPLTQKPHQQEMEVEQPC
  IQEVKRHMSDNRKSRSRSASRSPKRRRSRSGSRSRRSRHRRSRSRSRDRRRHSPRSRSQE
  RRDREKERERRQKGLPQVKPETASVCSTTLWVGQLDKRTTQQDVASLLEEFGPIESINMI
  PPRGCAYIVMVHRQDAYRALQKLSRGNYKVNQKSIKIAWALNKGIKADYKQYWDVELGVT
  YIPWDKVKPEELESFCEGGMLDSDTLNPDWKGIPKKPENEVAQNGGAETSHTEPVSPIPK
  PLPVPVPPIPVPAPITVPPPQVPPHQPGPPVVGALQPPAFTPPLGIPPPGFGPGVPPPPP
  PPPFLRPGFNPMHLPPGFLPPGPPPPITPPVSIPPPHTPPISIPNSTIAGINEDTTKDLS
  IGNPIPTVVSGARGNAESGDSVKMYGSAVPPAAPTNLPTPPVTQPVSLLGTQGVAPGPVI
  GLQAPSTGLLGARPGLIPLQRPPGMPPPHLQRFPLMPPRPMPPHMMHRGPPPGPGGFAMP
  PPHGMKGPFPPHGPFVRPGGMPGLGGPGPGPGGPEDRDGRQQPPQQPQQQPQPQAPQQPQ
  QQQQQQPPPSQQPPPTQQQPQQFRNDNRQQFNSGRDQERFGRRSFGNRVENDRERYGNRN
  DDRDNSNRDRREWGRRSPDRDRHRDLEERNRRSSGHRDRERDSRDRESRREKEEARGKEK
  PEVTDRAGGNKTVEPPISQVGNVDTASELEKGVSEAAVLKPSEELPAEATSSVEPEKDSG
  SAAEAPR
• Function: Anti-terminator protein required to prevent early mRNA termination during transcription. Together with SCAF8, acts by suppressing the use of early, alternative poly(A) sites, thereby preventing the accumulation of non-functional truncated proteins. Mechanistically, associates with the phosphorylated C-terminal heptapeptide repeat domain (CTD) of the largest RNA polymerase II subunit (POLR2A), and subsequently binds nascent RNA upstream of early polyadenylation sites to prevent premature mRNA transcript cleavage and polyadenylation. Independently of SCAF8, also acts as a suppressor of transcriptional readthrough.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complex neurodevelopmental disorder	DISB9AFI	Strong	Autosomal dominant	[1]
Diabetic kidney disease	DISJMWEY	Strong	Genetic Variation	[2]

12 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 SR-related and CTD-associated factor 4 (SCAF4).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of SR-related and CTD-associated factor 4 (SCAF4).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of SR-related and CTD-associated factor 4 (SCAF4).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of SR-related and CTD-associated factor 4 (SCAF4).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of SR-related and CTD-associated factor 4 (SCAF4).	[7]
Selenium	DM25CGV	Approved	Selenium decreases the expression of SR-related and CTD-associated factor 4 (SCAF4).	[8]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of SR-related and CTD-associated factor 4 (SCAF4).	[9]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of SR-related and CTD-associated factor 4 (SCAF4).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of SR-related and CTD-associated factor 4 (SCAF4).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of SR-related and CTD-associated factor 4 (SCAF4).	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of SR-related and CTD-associated factor 4 (SCAF4).	[12]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of SR-related and CTD-associated factor 4 (SCAF4).	[13]

References

• [1] Variants in SCAF4 Cause a Neurodevelopmental Disorder and Are Associated with Impaired mRNA Processing. Am J Hum Genet. 2020 Sep 3;107(3):544-554. doi: 10.1016/j.ajhg.2020.06.019. Epub 2020 Jul 29.
• [2] Multiple superoxide dismutase 1/splicing factor serine alanine 15 variants are associated with the development and progression of diabetic nephropathy: the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Genetics study.Diabetes. 2008 Jan;57(1):218-28. doi: 10.2337/db07-1059. Epub 2007 Oct 3.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [5] 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.
• [6] 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.
• [7] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [8] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [9] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [10] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [11] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [12] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [13] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.