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  • PMID: 28158788 was deleted because it is a duplicate of PMID: 27907888
Nucleic Acids Res. 2016 Oct 23. pii: gkw938. [Epub ahead of print]

A novel role for GSK3β as a modulator of Drosha microprocessor activity and MicroRNA biogenesis.

Author information

1
Imperial Centre for Translational and Experimental Medicine, Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
2
Medical Research Council Toxicology Unit, Hodgkin Building, Lancaster Road, Leicester, LE1 9HN, UK.
3
Imperial Centre for Translational and Experimental Medicine, Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK charlotte.bevan@imperial.ac.uk.

Abstract

Regulation of microRNA (miR) biogenesis is complex and stringently controlled. Here, we identify the kinase GSK3β as an important modulator of miR biogenesis at Microprocessor level. Repression of GSK3β activity reduces Drosha activity toward pri-miRs, leading to accumulation of unprocessed pri-miRs and reduction of pre-miRs and mature miRs without altering levels or cellular localisation of miR biogenesis proteins. Conversely, GSK3β activation increases Drosha activity and mature miR accumulation. GSK3β achieves this through promoting Drosha:cofactor and Drosha:pri-miR interactions: it binds to DGCR8 and p72 in the Microprocessor, an effect dependent upon presence of RNA. Indeed, GSK3β itself can immunoprecipitate pri-miRs, suggesting possible RNA-binding capacity. Kinase assays identify the mechanism for GSK3β-enhanced Drosha activity, which requires GSK3β nuclear localisation, as phosphorylation of Drosha at S300 and/or S302; confirmed by enhanced Drosha activity and association with cofactors, and increased abundance of mature miRs in the presence of phospho-mimic Drosha. Functional implications of GSK3β-enhanced miR biogenesis are illustrated by increased levels of GSK3β-upregulated miR targets following GSK3β inhibition. These data, the first to link GSK3β with the miR cascade in humans, highlight a novel pro-biogenesis role for GSK3β in increasing miR biogenesis as a component of the Microprocessor complex with wide-ranging functional consequences.

PMID:
27907888
PMCID:
PMC5389555
DOI:
10.1093/nar/gkw938

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