LAUSR

Significance Cells coordinate the rates of major biological processes in response to environmental conditions such as nutrient availability and temperature. Coordination mechanisms in which effects on one process are compensated for by effects on another process maintain an appropriate cellular balance. Here, we uncover a compensatory link between cleavage/polyadenylation, which generates poly(A) tails at mRNA 3′ ends, and mRNA decay. This compensatory link suggests that during cleavage/polyadenylation in the nucleus, mRNA isoforms are marked in a manner that persists upon translocation to the cytoplasm. This mark affects the activity of mRNA degradation machinery, thus influencing mRNA stability and allowing cells to maintain relatively similar levels of mRNA isoforms even when cleavage/polyadenylation rates change in response to environmental conditions. Cells have compensatory mechanisms to coordinate the rates of major biological processes, thereby permitting growth in a wide variety of conditions. Here, we uncover a compensatory link between cleavage/polyadenylation in the nucleus and messenger RNA (mRNA) turnover in the cytoplasm. On a global basis, same-gene 3′ mRNA isoforms with twofold or greater differences in half-lives have steady-state mRNA levels that differ by significantly less than a factor of 2. In addition, increased efficiency of cleavage/polyadenylation at a specific site is associated with reduced stability of the corresponding 3′ mRNA isoform. This inverse relationship between cleavage/polyadenylation and mRNA isoform half-life reduces the variability in the steady-state levels of mRNA isoforms, and it occurs in all four growth conditions tested. These observations suggest that during cleavage/polyadenylation in the nucleus, mRNA isoforms are marked in a manner that persists upon translocation to the cytoplasm and affects the activity of mRNA degradation machinery, thus influencing mRNA stability.