RNA-Binding Proteins which Affect mRNA Translation or Stability

The regulation of gene expression can take place at many stages subsequent to transcriptional activation. In eukaryotic systems the messenger RNA (mRNA) is subject to processing, nucleocytoplasmic transport, translation and degradation. Each of these points serves as a checkpoint at which the ultimate production of encoded protein can be regulated. Studies in the past two decades have shown that the modulation of mRNA stability plays an important role in regulating gene expression (1,2). In particular, factors that affect mRNA stability dictate whether the message half life is minutes or hours. This can underlie 1000-fold differences in the mRNA available for translation, and thus the amount of protein produced (3). Early alterations of the mRNA transcript are vital to its translational efficiency and stability. These include capping of the 5′ terminal nucleotide and polyadenylation of the 3′ end. The cap, which is an N7-methylated guanosine triphosphate, helps initiate pre-mRNA splicing, nucleocytoplasmic transport, mRNA end formation and translation, and protects the transcript from 5′ to 3′ exonucleases. Only when the 5′ cap is removed can degradation occur in a 5′ to 3′ direction. The poly-A tail is bound by the poly-A tail-binding protein (PABP) that assists with the initiation of translation. The poly-A tail also temporarily protects the coding region of the transcript from 3′ to 5′ exonucleases. mRNA stability is also dictated by the presence of specific cis-acting elements (e.g. AU-rich elements (AREs)), or other instability elements, most often located in their 3′ untranslated regions (UTRs) (4). AREs are generally 50 to 150 bases long and contain either one to three scattered copies of the AUUUA pentamer (class I), clustered and overlapped AUUUA repeats (class II), or contain long continuous U-rich regions (Class III). AREs have been found to direct mRNA degradation and thus play an important role in the regulation of gene expression. A number of proteins have been identified which specifically bind AREs and directly affect the stability of the mRNA. Likewise, the binding of proteins to poly-C motifs in the 3′ RNA-Binding Proteins which Affect mRNA Translation or Stability