Dynamic regulation of m⁶A deposition, poly(A) tails and CCR4-Not complex links transcription to mRNA stability

The stability of mRNA molecules is generally considered to be an intrinsic feature of every distinct transcript, mainly regulated by its tendency to bind various regulatory factors and the efficiency of its translation. In this study, we investigated the effect of transcription on the stability of multiple human and mouse mRNAs. We found that transcription positively regulates mRNA stability, rendering efficiently transcribed messengers less prone to degradation. We found this phenomenon to base on the co-transcriptionally deposited m6A modification, length of poly(A) tails, and the favorite activity of the CCR4-Not complex toward m6A-marked transcripts. Furthermore, it impacts lncRNAs and is insensitive to the expression levels.

Moreover, when transcription undergoes global changes, the cell counteracts them and buffers the mRNA levels accordingly. This response takes place upon exposure to genotoxic stress, energy deprivation, and activation of naïve B cells. Mechanistically, this phenomenon is based on the tightly and dynamically regulated expression of the degradation machinery in general and the CCR4-Not complex in particular. Remarkably, this regulatory pathway can impact the stabilities of thousands of mRNAs in parallel. Overall, these findings suggest transcription to be a primary regulator of mRNA degradation in eukaryotic cells and uncovers the central role of the coordination between these processes in the cellular response to multiple physiological conditions.