Recurrent Neurodevelopmentally Associated Variants of the Pre-mRNA Splicing Factor U2AF2 Alter RNA Binding Affinities and Interactions.

Autor:	Maji D; Department of Biochemistry and Biophysics, and the Center for RNA Biology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, United States., Jenkins JL; Department of Biochemistry and Biophysics, and the Center for RNA Biology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, United States., Boutz PL; Department of Biochemistry and Biophysics, and the Center for RNA Biology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, United States., Kielkopf CL; Department of Biochemistry and Biophysics, and the Center for RNA Biology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, United States.
Jazyk:	angličtina
Zdroj:	Biochemistry [Biochemistry] 2024 Nov 05; Vol. 63 (21), pp. 2718-2722. Date of Electronic Publication: 2024 Oct 10.
DOI:	10.1021/acs.biochem.4c00344
Abstrakt:	De novo mutations affecting the pre-mRNA splicing factor U2AF2 are associated with developmental delays and intellectual disabilities, yet the molecular basis is unknown. Here, we demonstrated by fluorescence anisotropy RNA binding assays that recurrent missense mutants (Arg149Trp, Arg150His, or Arg150Cys) decreased the binding affinity of U2AF2 for a consensus splice site RNA. Crystal structures at 1.4 Å resolutions showed that Arg149Trp or Arg150His disrupted hydrogen bonds between U2AF2 and the terminal nucleotides of the RNA site. Reanalysis of publicly available RNaseq data confirmed that U2AF2 depletion altered splicing of transcripts encoding RNA binding proteins (RBPs). These results confirmed that the impaired RNA interactions of Arg149Trp and Arg150His U2AF2 variants could contribute to dysregulating an RBP-governed neurodevelopmental program of alternative splicing.
Databáze:	MEDLINE
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