@article{d4abbe01a0734473938518015c3a1ede,
title = "Targeting Spt5-Pol II by Small-Molecule Inhibitors Uncouples Distinct Activities and Reveals Additional Regulatory Roles",
abstract = "Spt5 is a conserved and essential transcription elongation factor that promotes promoter-proximal pausing, promoter escape, elongation, and mRNA processing. Spt5 plays specific roles in the transcription of inflammation and stress-induced genes and tri-nucleotide expanded-repeat genes involved in inherited neurological pathologies. Here, we report the identification of Spt5-Pol II small-molecule inhibitors (SPIs). SPIs faithfully reproduced Spt5 knockdown effects on promoter-proximal pausing, NF-κB activation, and expanded-repeat huntingtin gene transcription. Using SPIs, we identified Spt5 target genes that responded with profoundly diverse kinetics. SPIs uncovered the regulatory role of Spt5 in metabolism via GDF15, a food intake- and body weight-inhibitory hormone. SPIs further unveiled a role for Spt5 in promoting the 3′ end processing of histone genes. While several SPIs affect all Spt5 functions, a few inhibit a single one, implying uncoupling and selective targeting of Spt5 activities. SPIs expand the understanding of Spt5-Pol II functions and are potential drugs against metabolic and neurodegenerative diseases.",
author = "Anat Bahat and Or Lahav and Dena Leshkowitz and Rivka Dikstein",
note = "This work was supported in part by grants from the Nella and Leon Benoziyo Center for Neurological Diseases, Yeda Research and Development Co. Ltd., the Estate of David Levinson, the Estate of Fannie Sherr, and the Israel Innovation Authority (KAMIN). We would like to thank Galit Cohen from the Maurice and Vivienne Wohl Institute for Drug Discovery of the Nancy and Stephen Grand Israel National Center for Personalized Medicine (G-INCPM) (Weizmann Institute of Science) for contributions to the drug screen, Dr. Sima Benjamin and Dr. Shlomit Gilad from the Crown Institute for Genomics of the G-INCPM for libraries preparation and RNA-seq services, Michael Gershovits from the Ilana and Pascal Mantoux Institute for Bioinformatics of the G-INCPM, Dr. Noa Wigoda from the Weizmann core facilities for the RNA-seq data analysis, and Mr. Arsenii Hordeichyk for technical assistance in the binding assays. R.D. is the incumbent of the Ruth and Leonard Simon Chair of Cancer Research. Author Contributions R.D. and A.B. conceived and designed the study, analyzed the data, and wrote the paper. A.B. carried out most of the experiments. O.L. provided technical assistance. A.P. and A.B. carried out the high-throughput drug screen. D.L. performed part of the bioinformatics analysis.",
year = "2019",
month = nov,
day = "21",
doi = "https://doi.org/10.1016/j.molcel.2019.08.024",
language = "الإنجليزيّة",
volume = "76",
pages = "617--631",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "4",
}