Localized Inhibition of Protein Phosphatase 1 by NUAK1 Promotes Spliceosome Activity and Reveals a MYC-Sensitive Feedback Control of Transcription

Mol Cell. 2020 Mar 19;77(6):1322-1339.e11. doi: 10.1016/j.molcel.2020.01.008. Epub 2020 Jan 31.


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.

Keywords: ARK5; MYC; NUAK1; PNUTS; PP1; Protein Phosphatase 1; Spliceosome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism*
  • Chromatin / genetics
  • Chromatin / metabolism*
  • Gene Expression Regulation
  • HeLa Cells
  • Humans
  • Mice
  • NIH 3T3 Cells
  • Phosphorylation
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Protein Phosphatase 1 / antagonists & inhibitors*
  • Protein Phosphatase 1 / genetics
  • Protein Phosphatase 1 / metabolism
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • RNA Polymerase II / genetics
  • RNA Polymerase II / metabolism
  • RNA Splicing
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Spliceosomes / genetics
  • Spliceosomes / metabolism*
  • Transcription, Genetic*


  • Chromatin
  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • Repressor Proteins
  • Protein Kinases
  • NUAK1 protein, human
  • RNA Polymerase II
  • Protein Phosphatase 1