Alteration of RNA Splicing by Small-Molecule Inhibitors of the Interaction between NHP2L1 and U4.

Autor:	Diouf B; 1 Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, TN, USA.; 2 Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA., Lin W; 3 Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA., Goktug A; 3 Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA., Grace CRR; 4 Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Waddell MB; 5 Molecular Interaction Analysis Shared Resource, St. Jude Children's Research Hospital, Memphis, TN, USA., Bao J; 1 Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, TN, USA.; 2 Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA., Shao Y; 6 Protein Production Facility, St. Jude Children's Research Hospital, Memphis, TN, USA., Heath RJ; 6 Protein Production Facility, St. Jude Children's Research Hospital, Memphis, TN, USA., Zheng JJ; 7 Stein Eye Institute and Department of Ophthalmology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA., Shelat AA; 3 Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA., Relling MV; 1 Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, TN, USA.; 2 Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA., Chen T; 3 Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA., Evans WE; 1 Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, TN, USA.; 2 Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
Jazyk:	angličtina
Zdroj:	SLAS discovery : advancing life sciences R & D [SLAS Discov] 2018 Feb; Vol. 23 (2), pp. 164-173. Date of Electronic Publication: 2017 Oct 06.
DOI:	10.1177/2472555217735035
Abstrakt:	Splicing is an important eukaryotic mechanism for expanding the transcriptome and proteome, influencing a number of biological processes. Understanding its regulation and identifying small molecules that modulate this process remain a challenge. We developed an assay based on time-resolved fluorescence resonance energy transfer (TR-FRET) to detect the interaction between the protein NHP2L1 and U4 RNA, which are two key components of the spliceosome. We used this assay to identify small molecules that interfere with this interaction in a high-throughput screening (HTS) campaign. Topotecan and other camptothecin derivatives were among the top hits. We confirmed that topotecan disrupts the interaction between NHP2L1 and U4 by binding to U4 and inhibits RNA splicing. Our data reveal new functions of known drugs that could facilitate the development of therapeutic strategies to modify splicing and alter gene function.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu