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

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.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002C-E88F-E Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002C-E894-F
Genre: Journal Article

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Sidarovich, A.1, Author              
Will, C. L.1, Author              
Anokhina, M. M.1, Author              
Ceballos, J., Author
Sievers, S., Author
Agafonov, D. E.1, Author              
Samatov, T.1, Author              
Bao, P.1, Author              
Kastner, B.1, Author              
Urlaub, H.2, Author              
Waldmann, H., Author
Lührmann, R.1, Author              
Affiliations:
1Department of Cellular Biochemistry, MPI for biophysical chemistry, Max Planck Society, ou_578576              
2Research Group of Bioanalytical Mass Spectrometry, MPI for biophysical chemistry, Max Planck Society, ou_578613              

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 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.

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Language(s): eng - English
 Dates: 2017-03-16
 Publication Status: Published online
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 Rev. Method: Peer
 Identifiers: DOI: 10.7554/eLife.23533.001
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Title: eLife
Source Genre: Journal
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Pages: 32 Volume / Issue: 6 Sequence Number: e23533 Start / End Page: - Identifier: -