Abstract
SummaryDeregulated 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.
Highlights
The MYC oncoprotein is a transcription factor that regulates broad programs of gene expression, promoting cell proliferation and cell growth and inducing major changes in growth-associated processes such as cellular metabolism and the interaction of cells with the micro-environment (Dang, 2012; Kress et al, 2015)
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
Summary
The MYC oncoprotein is a transcription factor that regulates broad programs of gene expression, promoting cell proliferation and cell growth and inducing major changes in growth-associated processes such as cellular metabolism and the interaction of cells with the micro-environment (Dang, 2012; Kress et al, 2015). Cells and tumors expressing deregulated levels of MYC rely on a number of specific factors for survival, including an enhanced dependence on anti-apoptotic proteins and trophic signals (Pelengaris et al, 2002), on glutamine as a nutrient source (Gao et al, 2009; Xiang et al, 2015), on splicing factors (Hsu et al, 2015), on cyclin-dependent kinases (Chipumuro et al, 2014; Christensen et al, 2014; Huang et al, 2014), and on AMP-dependent kinase (AMPK), which is activated by an increase in cellular AMP levels (Kfoury et al, 2018; Liu et al, 2012).
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
