Hakai is required for stabilization of core components of the m6A mRNA methylation machinery

Praveen Bawankar, Tina Lence, Chiara Paolantoni, Irmgard U. Haussmann, Migle Kazlauskiene, Dominik Jacob, Jan B. Heidelberger, Florian M. Richter, Mohanakarthik P. Nallasivan, Violeta Morin, Nastasja Kreim, Petra Beli, Mark Helm, Martin Jinek, Matthias Soller () and Jean-Yves Roignant ()
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Praveen Bawankar: Johannes Gutenberg-University Mainz
Tina Lence: Institute of Molecular Biology (IMB)
Chiara Paolantoni: University of Lausanne
Irmgard U. Haussmann: University of Birmingham
Migle Kazlauskiene: University of Zurich
Dominik Jacob: Johannes Gutenberg-University Mainz
Jan B. Heidelberger: Institute of Molecular Biology (IMB)
Florian M. Richter: Johannes Gutenberg-University Mainz
Mohanakarthik P. Nallasivan: University of Birmingham
Violeta Morin: Institute of Molecular Biology (IMB)
Nastasja Kreim: Institute of Molecular Biology (IMB)
Petra Beli: Institute of Molecular Biology (IMB)
Mark Helm: Johannes Gutenberg-University Mainz
Martin Jinek: University of Zurich
Matthias Soller: University of Birmingham
Jean-Yves Roignant: Johannes Gutenberg-University Mainz

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract N6-methyladenosine (m6A) is the most abundant internal modification on mRNA which influences most steps of mRNA metabolism and is involved in several biological functions. The E3 ubiquitin ligase Hakai was previously found in complex with components of the m6A methylation machinery in plants and mammalian cells but its precise function remained to be investigated. Here we show that Hakai is a conserved component of the methyltransferase complex in Drosophila and human cells. In Drosophila, its depletion results in reduced m6A levels and altered m6A-dependent functions including sex determination. We show that its ubiquitination domain is required for dimerization and interaction with other members of the m6A machinery, while its catalytic activity is dispensable. Finally, we demonstrate that the loss of Hakai destabilizes several subunits of the methyltransferase complex, resulting in impaired m6A deposition. Our work adds functional and molecular insights into the mechanism of the m6A mRNA writer complex.

Date: 2021
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DOI: 10.1038/s41467-021-23892-5

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