Cyclin B/CDK1 and Cyclin A/CDK2 phosphorylate DENR to promote mitotic protein translation and faithful cell division

Katharina Clemm Von Hohenberg,Sandra Müller,Thomas G Hofmann,Aurelio A Teleman,Matthias Meister,Jonathan Bohlen,Sibylle Schleich

doi:10.1038/s41467-022-28265-0

Abstract

DENR and MCTS1 have been identified as oncogenes in several different tumor entities. The heterodimeric DENR·MCTS1 protein complex promotes translation of mRNAs containing upstream Open Reading Frames (uORFs). We show here that DENR is phosphorylated on Serine 73 by Cyclin B/CDK1 and Cyclin A/CDK2 at the onset of mitosis, and then dephosphorylated as cells exit mitosis. Phosphorylation of Ser73 promotes mitotic stability of DENR protein and prevents its cleavage at Asp26. This leads to enhanced translation of mRNAs involved in mitosis. Indeed, we find that roughly 40% of all mRNAs with elevated translation in mitosis are DENR targets. In the absence of DENR or of Ser73 phosphorylation, cells display elevated levels of aberrant mitoses and cell death. This provides a mechanism how the cell cycle regulates translation of a subset of mitotically relevant mRNAs during mitosis.

Highlights

DENR and MCTS1 have been identified as oncogenes in several different tumor entities
We previously showed that the DENR·MCTS1 complex promotes “translation re-initiation” on mRNAs containing upstream Open Reading Frames[30,36]
We find that DENR undergoes CDK1- and CDK2-dependent phosphorylation on Ser[73] in mitosis to promote translation of specific mitotic target genes that enable timely and faithful cell division and mitotic cell survival

Summary

Introduction

DENR and MCTS1 have been identified as oncogenes in several different tumor entities. Phosphorylation of Ser[73] promotes mitotic stability of DENR protein and prevents its cleavage at Asp[26] This leads to enhanced translation of mRNAs involved in mitosis. In the absence of DENR or of Ser[73] phosphorylation, cells display elevated levels of aberrant mitoses and cell death This provides a mechanism how the cell cycle regulates translation of a subset of mitotically relevant mRNAs during mitosis. DENR and MCTS1 act in a pro-proliferative and protumorigenic manner and appear to do so by modulating translation of mRNAs containing uORFs. One important open question is whether and how activity of the DENR·MCTS1 protein complex is regulated. We find that DENR undergoes CDK1- and CDK2-dependent phosphorylation on Ser[73] in mitosis to promote translation of specific mitotic target genes that enable timely and faithful cell division and mitotic cell survival

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