Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLQ1ZLS)

• DOT Name: 17S U2 SnRNP complex component HTATSF1 (HTATSF1)
• Synonyms: HIV Tat-specific factor 1; Tat-SF1
• Gene Name: HTATSF1
• UniProt ID: HTSF1_HUMAN
• PDB ID: 2DIT; 6N3D; 6N3E; 6N3F; 6NSX; 6Y50; 6Y53; 6Y5Q; 7EVO; 7Q3L; 8HK1
• Pfam ID: PF00076
• Sequence:
  MSGTNLDGNDEFDEQLRMQELYGDGKDGDTQTDAGGEPDSLGQQPTDTPYEWDLDKKAWF
  PKITEDFIATYQANYGFSNDGASSSTANVEDVHARTAEEPPQEKAPEPTDARKKGEKRKA
  ESGWFHVEEDRNTNVYVSGLPPDITVDEFIQLMSKFGIIMRDPQTEEFKVKLYKDNQGNL
  KGDGLCCYLKRESVELALKLLDEDEIRGYKLHVEVAKFQLKGEYDASKKKKKCKDYKKKL
  SMQQKQLDWRPERRAGPSRMRHERVVIIKNMFHPMDFEDDPLVLNEIREDLRVECSKFGQ
  IRKLLLFDRHPDGVASVSFRDPEEADYCIQTLDGRWFGGRQITAQAWDGTTDYQVEETSR
  EREERLRGWEAFLNAPEANRGLRRSDSVSASERAGPSRARHFSEHPSTSKMNAQETATGM
  AFEEPIDEKKFEKTEDGGEFEEGASENNAKESSPEKEAEEGCPEKESEEGCPKRGFEGSC
  SQKESEEGNPVRGSEEDSPKKESKKKTLKNDCEENGLAKESEDDLNKESEEEVGPTKESE
  EDDSEKESDEDCSEKQSEDGSEREFEENGLEKDLDEEGSEKELHENVLDKELEENDSENS
  EFEDDGSEKVLDEEGSEREFDEDSDEKEEEEDTYEKVFDDESDEKEDEEYADEKGLEAAD
  KKAEEGDADEKLFEESDDKEDEDADGKEVEDADEKLFEDDDSNEKLFDEEEDSSEKLFDD
  SDERGTLGGFGSVEEGPLSTGSSFILSSDDDDDDI
• Function: Component of the 17S U2 SnRNP complex of the spliceosome, a large ribonucleoprotein complex that removes introns from transcribed pre-mRNAs. The 17S U2 SnRNP complex (1) directly participates in early spliceosome assembly and (2) mediates recognition of the intron branch site during pre-mRNA splicing by promoting the selection of the pre-mRNA branch-site adenosine, the nucleophile for the first step of splicing. Within the 17S U2 SnRNP complex, HTATSF1 is required to stabilize the branchpoint-interacting stem loop. HTATSF1 is displaced from the 17S U2 SnRNP complex before the stable addition of the 17S U2 SnRNP complex to the spliceosome, destabilizing the branchpoint-interacting stem loop and allowing to probe intron branch site sequences. Also acts as a regulator of transcriptional elongation, possibly by mediating the reciprocal stimulatory effect of splicing on transcriptional elongation. Involved in double-strand break (DSB) repair via homologous recombination in S-phase by promoting the recruitment of TOPBP1 to DNA damage sites. Mechanistically, HTATSF1 is (1) recruited to DNA damage sites in S-phase via interaction with poly-ADP-ribosylated RPA1 and (2) phosphorylated by CK2, promoting recruitment of TOPBP1, thereby facilitating RAD51 nucleofilaments formation and RPA displacement, followed by homologous recombination ; (Microbial infection) In case of infection by HIV-1, it is up-regulated by the HIV-1 proteins NEF and gp120, acts as a cofactor required for the Tat-enhanced transcription of the virus.
• Tissue Specificity: Widely expressed.
• Reactome Pathway: mRNA Splicing - Major Pathway (R-HSA-72163)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	17S U2 SnRNP complex component HTATSF1 (HTATSF1) increases the response to substance of Arsenic trioxide.	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of 17S U2 SnRNP complex component HTATSF1 (HTATSF1).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of 17S U2 SnRNP complex component HTATSF1 (HTATSF1).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of 17S U2 SnRNP complex component HTATSF1 (HTATSF1).	[9]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of 17S U2 SnRNP complex component HTATSF1 (HTATSF1).	[10]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of 17S U2 SnRNP complex component HTATSF1 (HTATSF1).	[11]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of 17S U2 SnRNP complex component HTATSF1 (HTATSF1).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of 17S U2 SnRNP complex component HTATSF1 (HTATSF1).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of 17S U2 SnRNP complex component HTATSF1 (HTATSF1).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 17S U2 SnRNP complex component HTATSF1 (HTATSF1).	[4]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of 17S U2 SnRNP complex component HTATSF1 (HTATSF1).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of 17S U2 SnRNP complex component HTATSF1 (HTATSF1).	[7]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of 17S U2 SnRNP complex component HTATSF1 (HTATSF1).	[8]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of 17S U2 SnRNP complex component HTATSF1 (HTATSF1).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of 17S U2 SnRNP complex component HTATSF1 (HTATSF1).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of 17S U2 SnRNP complex component HTATSF1 (HTATSF1).	[14]

References

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• [10] 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.
• [11] 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.
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• [15] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.