Differential mRNA stability to reticulocyte ribonucleases correlates with 3′ non‐coding (U)_nA sequences

The stabilities of different mRNA species were analyzed in a reticulocyte lysate system under protein‐synthesizing conditions. In all cases examined the relative mRNA degradation by reticulocyte ribonucleases as well as by the interferon‐modulated (2′‐5′) (A)_n‐dependent endonuclease correlated with the extent of (U)_nA sequences within the 3′ non‐coding region. The experimental data presented indicate that according to their stabilities at least three major mRNA groups may be identified: (a) (U)_nA‐poor mRNAs (e.g. globin) are essentially stable and are only slightly degraded by the (2′‐5′)(A)_n‐dependent endonuclease; (b) mRNA species with intermediate (U)_nA levels (e.g. Igα and Igμ heavy‐chain mRNAs) are partially degraded by general ribonuclease activity and further degraded by the (2′‐5′)(A)_n‐dependent endonuclease and (c) (U)_nA‐rich mRNA species (such as c‐myc and non‐skeletal actin mRNAs) are inherently unstable and are extremely sensitive to degradation by general ribonuclease activity. A survey of mRNA nucleotide sequences demonstrated that without exception (U)_nA‐rich stretches appeared more frequently within the 3′ non‐coding region than in the coding or 5′ non‐coding regions. A comparison of 3′ non‐coding region sequences from 92 different mRNAs revealed that transiently expressed mRNAs, such as the interleukins, nerve growth factor, epidermal growth factor receptor, c‐myc, c‐fos, c‐myb and several other oncogenes as well as interferons α, β and γ were exceptially (U)_nA‐rich. It is postulated that differential mRNA stability may be partly determined by the primary nucleotide sequence and in particular by (U)_nA sequences within the 3′ non‐coding region. This may represent a novel post‐transcriptional strategy employed by the cell to selectively retain or destroy discrete mRNA species.