CDK1-Cyclin B1 Activates RNMT, Coordinating mRNA Cap Methylation with G1 Phase Transcription

Michael Aregger,Aneesa Kaskar,Dhaval Varshney,Maria Elena Fernandez-Sanchez,Francisco A Inesta-Vaquera,Simone Weidlich,Victoria H Cowling

doi:10.1016/j.molcel.2016.02.008

Michael Aregger, Aneesa Kaskar + Show 5 more

Open Access

https://doi.org/10.1016/j.molcel.2016.02.008

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Journal: Molecular Cell	Publication Date: Mar 1, 2016
Citations: 44	License type: cc-by

Affiliation: University of Dundee

Abstract

SummaryThe creation of translation-competent mRNA is dependent on RNA polymerase II transcripts being modified by addition of the 7-methylguanosine (m7G) cap. The factors that mediate splicing, nuclear export, and translation initiation are recruited to the transcript via the cap. The cap structure is formed by several activities and completed by RNMT (RNA guanine-7 methyltransferase), which catalyzes N7 methylation of the cap guanosine. We report that CDK1-cyclin B1 phosphorylates the RNMT regulatory domain on T77 during G2/M phase of the cell cycle. RNMT T77 phosphorylation activates the enzyme both directly and indirectly by inhibiting interaction with KPNA2, an RNMT inhibitor. RNMT T77 phosphorylation results in elevated m7G cap methyltransferase activity at the beginning of G1 phase, coordinating mRNA capping with the burst of transcription that occurs following nuclear envelope reformation. RNMT T77 phosphorylation is required for the production of cohort of proteins, and inhibiting T77 phosphorylation reduces the cell proliferation rate.

Highlights

Maturation of RNA polymerase II transcripts into translationcompetent mRNA is dependent on addition of the 7-methylguanosine (m7G) cap to the first transcribed nucleotide (Shuman, 2015; Topisirovic et al, 2011)
The methyltransferase activity resides in a separate complex, RNMT-RAM, which consists of a catalytic subunit, RNA guanine-7 methyltransferase (RNMT), and an activating subunit, RNMT-activating miniprotein (RAM) (Gonatopoulos-Pournatzis et al, 2011; Pillutla et al, 1998; Tsukamoto et al, 1998)
We report that RNMT is phosphorylated and activated by CDK1-cyclin B1, resulting in elevated cap methyltransferase activity when transcription is reinitiating after mitosis

Summary

Introduction

Maturation of RNA polymerase (pol) II transcripts into translationcompetent mRNA is dependent on addition of the 7-methylguanosine (m7G) cap to the first transcribed nucleotide (Shuman, 2015; Topisirovic et al, 2011). The resultant m7G cap protects transcripts from exonucleases and is a docking site for the cap binding complex (CBC), eukaryotic initiation factor 4F (eIF4F), and other complexes that mediate transcript splicing, polyadenylation, nuclear export, and translation initiation (Gonatopoulos-Pournatzis and Cowling, 2014; Topisirovic et al, 2011). RNMT contains a regulatory domain that affects catalytic activity and recruits RNMT-RAM to transcription initiation sites (Aregger and Cowling, 2013)

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