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  Localized inhibition of protein phosphatase 1 by NUAK1 promotes spliceosome activity and reveals a MYC-sensitive feedback control of transcription.

Cossa, G., Roeschert, I., Prinz, F., Baluapuri, A., Silveira Vidal, R., Schülein-Völk, C., et al. (2020). Localized inhibition of protein phosphatase 1 by NUAK1 promotes spliceosome activity and reveals a MYC-sensitive feedback control of transcription. Molecular Cell, (in press). doi: 10.1016/j.molcel.2020.01.008.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0005-9971-F Version Permalink: http://hdl.handle.net/21.11116/0000-0005-9974-C
Genre: Journal Article

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Cossa, G., Author
Roeschert, I., Author
Prinz, F., Author
Baluapuri, A., Author
Silveira Vidal, R., Author
Schülein-Völk, C., Author
Chang, Y. C., Author
Ade, C. P., Author
Mastrobuoni, G., Author
Girard, C., Author
Wortmann, L., Author
Walz, S., Author
Lührmann, R.1, Author              
Kempa, S., Author
Kuster, B., Author
Wolf, E., Author
Mumberg, D., Author
Eilers, M., Author
Affiliations:
1Department of Cellular Biochemistry, MPI for biophysical chemistry, Max Planck Society, ou_578576              

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Free keywords: ARK5; MYC; NUAK1; PNUTS; PP1; Protein Phosphatase 1; Spliceosome
 Abstract: Deregulated expression of MYC induces a dependence on the NUAK1 kinase, but the molecular mechanisms underlying this dependence have not been fully clarified. Here, we show that NUAK1 is a predominantly nuclear protein that associates with a network of nuclear protein phosphatase 1 (PP1) interactors and that PNUTS, a nuclear regulatory subunit of PP1, is phosphorylated by NUAK1. Both NUAK1 and PNUTS associate with the splicing machinery. Inhibition of NUAK1 abolishes chromatin association of PNUTS, reduces spliceosome activity, and suppresses nascent RNA synthesis. Activation of MYC does not bypass the requirement for NUAK1 for spliceosome activity but significantly attenuates transcription inhibition. Consequently, NUAK1 inhibition in MYC-transformed cells induces global accumulation of RNAPII both at the pause site and at the first exon-intron boundary but does not increase mRNA synthesis. We suggest that NUAK1 inhibition in the presence of deregulated MYC traps non-productive RNAPII because of the absence of correctly assembled spliceosomes.

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Language(s): eng - English
 Dates: 2020-01-31
 Publication Status: Published online
 Pages: -
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 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1016/j.molcel.2020.01.008
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Title: Molecular Cell
Source Genre: Journal
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