A synthetic small molecule stalls pre-mRNA splicing by promoting an early-stage U2AF2-RNA complex.

Autor: Chatrikhi R; Department of Biochemistry and Biophysics and Center for RNA Biology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14620, USA., Feeney CF; Department of Biochemistry and Biophysics and Center for RNA Biology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14620, USA., Pulvino MJ; Department of Biochemistry and Biophysics and Center for RNA Biology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14620, USA., Alachouzos G; Department of Chemistry, University of Rochester, Rochester, NY 14627, USA., MacRae AJ; Department of Molecular, Cell and Developmental Biology and Center for Molecular Biology of RNA, University of California Santa Cruz, Santa Cruz, CA 95064, USA., Falls Z; Department of Medical Informatics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14214, USA., Rai S; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02114, USA., Brennessel WW; Department of Chemistry, University of Rochester, Rochester, NY 14627, USA., Jenkins JL; Department of Biochemistry and Biophysics and Center for RNA Biology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14620, USA., Walter MJ; Department of Medicine, Washington University, St. Louis, MO 63110, USA., Graubert TA; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02114, USA., Samudrala R; Department of Medical Informatics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14214, USA., Jurica MS; Department of Molecular, Cell and Developmental Biology and Center for Molecular Biology of RNA, University of California Santa Cruz, Santa Cruz, CA 95064, USA., Frontier AJ; Department of Chemistry, University of Rochester, Rochester, NY 14627, USA., Kielkopf CL; Department of Biochemistry and Biophysics and Center for RNA Biology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14620, USA. Electronic address: clara_kielkopf@urmc.rochester.edu.
Jazyk: angličtina
Zdroj: Cell chemical biology [Cell Chem Biol] 2021 Aug 19; Vol. 28 (8), pp. 1145-1157.e6. Date of Electronic Publication: 2021 Mar 08.
DOI: 10.1016/j.chembiol.2021.02.007
Abstrakt: Dysregulated pre-mRNA splicing is an emerging Achilles heel of cancers and myelodysplasias. To expand the currently limited portfolio of small-molecule drug leads, we screened for chemical modulators of the U2AF complex, which nucleates spliceosome assembly and is mutated in myelodysplasias. A hit compound specifically enhances RNA binding by a U2AF2 subunit. Remarkably, the compound inhibits splicing of representative substrates and stalls spliceosome assembly at the stage of U2AF function. Computational docking, together with structure-guided mutagenesis, indicates that the compound bridges the tandem U2AF2 RNA recognition motifs via hydrophobic and electrostatic moieties. Cells expressing a cancer-associated U2AF1 mutant are preferentially killed by treatment with the compound. Altogether, our results highlight the potential of trapping early spliceosome assembly as an effective pharmacological means to manipulate pre-mRNA splicing. By extension, we suggest that stabilizing assembly intermediates may offer a useful approach for small-molecule inhibition of macromolecular machines.
Competing Interests: Declaration of interests The authors declare no competing interests.
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Databáze: MEDLINE