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Journal Article

Identification of a small molecule inhibitor that stalls splicing at an early step of spliceosome activation.

MPS-Authors
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Sidarovich,  A.
Department of Cellular Biochemistry, MPI for biophysical chemistry, Max Planck Society;

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Will,  C. L.
Department of Cellular Biochemistry, MPI for biophysical chemistry, Max Planck Society;

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Anokhina,  M. M.
Department of Cellular Biochemistry, MPI for biophysical chemistry, Max Planck Society;

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Agafonov,  D. E.
Department of Cellular Biochemistry, MPI for biophysical chemistry, Max Planck Society;

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Samatov,  T.
Department of Cellular Biochemistry, MPI for biophysical chemistry, Max Planck Society;

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Bao,  P.
Department of Cellular Biochemistry, MPI for biophysical chemistry, Max Planck Society;

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Kastner,  B.
Department of Cellular Biochemistry, MPI for biophysical chemistry, Max Planck Society;

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Urlaub,  H.
Research Group of Bioanalytical Mass Spectrometry, MPI for biophysical chemistry, Max Planck Society;

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Lührmann,  R.
Department of Cellular Biochemistry, MPI for biophysical chemistry, Max Planck Society;

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Fulltext (public)

2418361.pdf
(Publisher version), 7MB

Supplementary Material (public)

2418361_Suppl.docx
(Supplementary material), 431KB

Citation

Sidarovich, A., Will, C. L., Anokhina, M. M., Ceballos, J., Sievers, S., Agafonov, D. E., et al. (2017). Identification of a small molecule inhibitor that stalls splicing at an early step of spliceosome activation. eLife, 6: e23533. doi:10.7554/eLife.23533.001.


Cite as: http://hdl.handle.net/11858/00-001M-0000-002C-E88F-E
Abstract
Small molecule inhibitors of pre-mRNA splicing are important tools for identifying new spliceosome assembly intermediates, allowing a finer dissection of spliceosome dynamics and function. Here, we identified a small molecule that inhibits human pre-mRNA splicing at an intermediate stage during conversion of pre-catalytic spliceosomal B complexes into activated Bact complexes. Characterization of the stalled complexes (designated B028) revealed that U4/U6 snRNP proteins are released during activation before the U6 Lsm and B-specific proteins, and before recruitment and/or stable incorporation of Prp19/CDC5L complex and other Bact complex proteins. The U2/U6 RNA network in B028 complexes differs from that of the Bact complex, consistent with the idea that the catalytic RNA core forms stepwise during the B to Bact transition and is likely stabilized by the Prp19/CDC5L complex and related proteins. Taken together, our data provide new insights into the RNP rearrangements and extensive exchange of proteins that occurs during spliceosome activation.