Localized Inhibition of Protein Phosphatase 1 by NUAK1 Promotes Spliceosome Activity and Reveals a MYC-Sensitive Feedback Control of Transcription.
Animals
Cell Nucleus
/ genetics
Chromatin
/ genetics
Gene Expression Regulation
HeLa Cells
Humans
Mice
NIH 3T3 Cells
Phosphorylation
Protein Kinases
/ genetics
Protein Phosphatase 1
/ antagonists & inhibitors
Proto-Oncogene Proteins c-myc
/ genetics
RNA Polymerase II
/ genetics
RNA Splicing
Repressor Proteins
/ genetics
Spliceosomes
/ genetics
Transcription, Genetic
ARK5
MYC
NUAK1
PNUTS
PP1
Protein Phosphatase 1
Spliceosome
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
19 03 2020
19 03 2020
Historique:
received:
02
05
2019
revised:
09
12
2019
accepted:
07
01
2020
pubmed:
2
2
2020
medline:
15
7
2020
entrez:
2
2
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32006464
pii: S1097-2765(20)30008-3
doi: 10.1016/j.molcel.2020.01.008
pmc: PMC7086158
pii:
doi:
Substances chimiques
Chromatin
0
MYC protein, human
0
Proto-Oncogene Proteins c-myc
0
Repressor Proteins
0
Protein Kinases
EC 2.7.-
NUAK1 protein, human
EC 2.7.1.-
RNA Polymerase II
EC 2.7.7.-
Protein Phosphatase 1
EC 3.1.3.16
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1322-1339.e11Commentaires et corrections
Type : CommentIn
Type : CommentIn
Type : ErratumIn
Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests L.W., F.P., and D.M. are employees and shareholders of Bayer AG. The other authors declare no competing interests.
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