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A single synonymous mutation determines the phosphorylation and stability of the nascent protein
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2019 (English)In: Journal of Molecular Cell Biology, ISSN 1674-2788, E-ISSN 1759-4685, Vol. 11, no 3, p. 187-199Article in journal (Refereed) Published
Abstract [en]

p53 is an intrinsically disordered protein with a large number of post-translational modifications and interacting partners. The hierarchical order and subcellular location of these events are still poorly understood. The activation of p53 during the DNA damage response (DDR) requires a switch in the activity of the E3 ubiquitin ligase MDM2 from a negative to a positive regulator of p53. This is mediated by the ATM kinase that regulates the binding of MDM2 to the p53 mRNA facilitating an increase in p53 synthesis. Here we show that the binding of MDM2 to the p53 mRNA brings ATM to the p53 polysome where it phosphorylates the nascent p53 at serine 15 and prevents MDM2-mediated degradation of p53. A single synonymous mutation in p53 codon 22 (L22L) prevents the phosphorylation of the nascent p53 protein and the stabilization of p53 following genotoxic stress. The ATM trafficking from the nucleus to the p53 polysome is mediated by MDM2, which requires its interaction with the ribosomal proteins RPL5 and RPL11. These results show how the ATM kinase phosphorylates the p53 protein while it is being synthesized and offer a novel mechanism whereby a single synonymous mutation controls the stability and activity of the encoded protein.

Place, publisher, year, edition, pages
Oxford University Press, 2019. Vol. 11, no 3, p. 187-199
Keywords [en]
synonymous mutations, intrinsically disordered proteins, cell signaling, MDM2, p53 messenger RNA, ATM kinase
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-159634DOI: 10.1093/jmcb/mjy049ISI: 000467903600002PubMedID: 30252118OAI: oai:DiVA.org:umu-159634DiVA, id: diva2:1323475
Available from: 2019-06-12 Created: 2019-06-12 Last updated: 2019-06-12Bibliographically approved

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Wang, LixiaoFåhraeus, Robin

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CiteExportLink to record
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