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

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.

Transcriptome analysis of the binucleate ciliate Tetrahymena thermophila with asynchronous nuclear cell cycles

“…Decades of research in yeast and mammalian cells have uncovered the many layers of regulation needed to ensure the fidelity of cell cycle transitions and ensuing stage-specific processes (i.e., DNA replication, chromosome segregation, cell division). They include cell cycle–regulated transcription, translational control of mRNAs, activation of proteins by phosphorylation, and ubiquitin-mediated protein degradation ( Stumpf et al ., 2013 ; reviewed in Benanti, 2016 ; Blank et al ., 2017 ; reviewed in Zou and Lin, 2021 ; Clemm von Hohenberg et al ., 2022 ). Posttranslational protein modification and turnover are critical for generating sharp cell cycle transitions.…”

Interaction of a Novel Alternatively Spliced Variant of HSD11B1L with Parkin Enhances the Carcinogenesis Potential of Glioblastoma: Peiminine Interferes with This Interaction

“…The M phase requires the interaction with cyclin A-CDK1. Cyclin B-CDK1 is required for cells to enter and exit the M phase of the cell cycle [ 35 ]. Rouland et al indicated that parkin expression was lessened in GBM specimens and that its expression was inversely correlated with that of cyclins A and B [ 28 ].…”

Dysregulated genes in undifferentiated spermatogonia and Sertoli cells are associated with the spermatogenic arrest in cattleyak

“…Therefore, we believe that spermatogenesis in CY only progresses to the meiosis I and arrests at early meiotic stage, resulting in almost no secondary spermatocytes, haploid spermatids and sperm in its testis. DENR can be phosphorylated by CDK1 and CDK2, which promotes the translation of mitotic genes and enables the timely and reliable division of cells (Clemm von Hohenberg et al, 2022). Its expression level in the testis of CY was higher, which might be due to the blocked meiosis process and relatively exuberant mitosis of CY.…”

“…The scale bar is 100 μm. (c) Western Blot of GATA4 in Sertoil cells of YK and CY translation of mitotic genes and enables the timely and reliable division of cells (Clemm von Hohenberg et al, 2022). Its expression level in the testis of CY was higher, which might be due to the blocked meiosis process and relatively exuberant mitosis of CY.…”