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bioRxiv · 10.64898/2026.01.10.698208

Lysine acetylation facilitates competitive recruitment of translation termination factor eRF3a by PABPC1 C-terminal domain

Dubiez, E.·Yeung, Y. T.·Chapman, T.·Soetens, M.·Virdee, S. G.·Cook, A. G.·Gray, N. K.·Brook, M.
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Abstract

In eukaryotic cells, almost all mRNA transcripts are polyadenylated in the nucleus, with the poly(A)-tail being critical for their export, translation and stability. PABPC1 is a multifunctional RNA-binding protein (RBP) that binds poly(A)-tails and is a key driver of mRNA post-transcriptional regulation. It achieves this in part by interacting with a broad range of PAM2-motif containing proteins that bind the same common site within PABPC1s PABC domain but result in diverse regulatory outcomes. Regulation of this intricate network of interactions remains poorly understood but our previous studies revealed the regulatory potential of mutually-exclusive acetylation or dimethylation of a key lysine sidechain (K606). To address this, we undertook a systematic study of PAM2-motifs, identifying translation termination factor eRF3a and translation repressor PAIP2 as having a >ten-fold higher affinity for PABPC1 relative to eleven other PAM2-motif partner proteins. Acetylation of PABPC1 at K606 specifically enhances its affinity for eRF3a in vitro, and we present the crystal structure of the specifically K606 acetylated C-terminal domain of PABPC1 in complex with the PAM2 motif of eRF3a, providing structural and functional insights into how acetylation facilitates competitive eRF3a recruitment to PABPC1 and mRNA. We further demonstrate that K606 acetylation promotes PABPC1-eRF3a interaction in cells, thereby antagonising other PAM2-dependent RNA effectors. Taken together, our results show that acetylation of lysine 606 in the PABC domain can specifically modulate PABPC1 partner selectivity, providing crucial insight into how PABPC1 multifunctionality can be regulated to coordinate mRNA usage and fate in the cytoplasm.

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Dubiez, E., Yeung, Y. T., Chapman, T., Soetens, M., Virdee, S. G., Cook, A. G., Gray, N. K., Brook, M.. 2026-01-11. Lysine acetylation facilitates competitive recruitment of translation termination factor eRF3a by PABPC1 C-terminal domain. https://doi.org/10.64898/2026.01.10.698208

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