Genome-scale conserved molecular principles of mRNA half-life regulation

Precise control of protein and mRNA degradation is essential for cellular metabolism and homeostasis. Controlled and specific degradation of both molecular species necessitates their engagements with the respective degradation machineries; this engagement involves a disordered/unstructured segment of the substrate traversing the degradation tunnel of the machinery and accessing the catalytic sites. Here, we report that mRNAs comprising longer terminal and/or internal unstructured segments have significantly shorter half-lives; the lengths of the 5′ terminal, 3′ terminal and internal unstructured segments that affect mRNA half-life are compatible with molecular structures of the 5′ exo- 3′ exo- and endo-ribonuclease machineries. Sequestration into ribonucleoprotein complexes elongates mRNA half-life, presumably by burying ribonuclease engagement sites under oligomeric interfaces. After gene duplication, differences in terminal unstructured lengths, proportions of internal unstructured segments and oligomerization modes result in significantly altered half-lives of paralogous mRNAs. Side-by-side comparison of molecular principles underlying controlled protein and mRNA degradation unravels their remarkable mechanistic similarities, and suggests how the intrinsic structural features of the two molecular species regulate their half-lives on genome-scale and during evolution.