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- Title
MYC dephosphorylation by the PP1/PNUTS phosphatase complex regulates chromatin binding and protein stability.
- Authors
Dingar, Dharmendra; Tu, William B.; Resetca, Diana; Lourenco, Corey; Tamachi, Aaliya; De Melo, Jason; Houlahan, Kathleen E.; Kalkat, Manpreet; Chan, Pak-Kei; Boutros, Paul C.; Raught, Brian; Penn, Linda Z.
- Abstract
The c-MYC (MYC) oncoprotein is deregulated in over 50% of cancers, yet regulatory mechanisms controlling MYC remain unclear. To this end, we interrogated the MYC interactome using BioID mass spectrometry (MS) and identified PP1 (protein phosphatase 1) and its regulatory subunit PNUTS (protein phosphatase-1 nuclear-targeting subunit) as MYC interactors. We demonstrate that endogenous MYC and PNUTS interact across multiple cell types and that they co-occupy MYC target gene promoters. Inhibiting PP1 by RNAi or pharmacological inhibition results in MYC hyperphosphorylation at multiple serine and threonine residues, leading to a decrease in MYC protein levels due to proteasomal degradation through the canonical SCFFBXW7 pathway. MYC hyperphosphorylation can be rescued specifically with exogenous PP1, but not other phosphatases. Hyperphosphorylated MYC retained interaction with its transcriptional partner MAX, but binding to chromatin is significantly compromised. Our work demonstrates that PP1/PNUTS stabilizes chromatin-bound MYC in proliferating cells. Deregulated MYC activity is oncogenic and is deregulated in a large fraction of human cancers. Here the authors find that protein phosphatase 1 and its regulatory subunit PNUTS controls MYC stability and its interaction with chromatin.
- Publication
Nature Communications, 2018, Vol 9, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-018-05660-0