RNF219 attenuates global mRNA decay through inhibition of CCR4-NOT complex-mediated deadenylation

Fabian Poetz, Joshua Corbo, Yevgen Levdansky, Alexander Spiegelhalter, Doris Lindner, Vera Magg, Svetlana Lebedeva, Jörg Schweiggert, Johanna Schott, Eugene Valkov () and Georg Stoecklin ()
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Fabian Poetz: Heidelberg University
Joshua Corbo: National Cancer Institute (NCI)
Yevgen Levdansky: National Cancer Institute (NCI)
Alexander Spiegelhalter: Heidelberg University
Doris Lindner: Heidelberg University
Vera Magg: Heidelberg University
Svetlana Lebedeva: Berlin Institute for Molecular Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine
Jörg Schweiggert: Center for Molecular Biology of Heidelberg University (ZMBH), German Cancer Research Center (DKFZ)-ZMBH Alliance
Johanna Schott: Heidelberg University
Eugene Valkov: National Cancer Institute (NCI)
Georg Stoecklin: Heidelberg University

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: Abstract The CCR4-NOT complex acts as a central player in the control of mRNA turnover and mediates accelerated mRNA degradation upon HDAC inhibition. Here, we explored acetylation-induced changes in the composition of the CCR4-NOT complex by purification of the endogenously tagged scaffold subunit NOT1 and identified RNF219 as an acetylation-regulated cofactor. We demonstrate that RNF219 is an active RING-type E3 ligase which stably associates with CCR4-NOT via NOT9 through a short linear motif (SLiM) embedded within the C-terminal low-complexity region of RNF219. By using a reconstituted six-subunit human CCR4-NOT complex, we demonstrate that RNF219 inhibits deadenylation through the direct interaction of the α-helical SLiM with the NOT9 module. Transcriptome-wide mRNA half-life measurements reveal that RNF219 attenuates global mRNA turnover in cells, with differential requirement of its RING domain. Our results establish RNF219 as an inhibitor of CCR4-NOT-mediated deadenylation, whose loss upon HDAC inhibition contributes to accelerated mRNA turnover.

Date: 2021
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DOI: 10.1038/s41467-021-27471-6

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