Cell cycle control (and more) by programmed −1 ribosomal frameshifting: implications for disease and therapeutics

Belew, Ashton T; Dinman, Jonathan D

Like most basic molecular mechanisms, programmed –1 ribosomal frameshifting (−1 PRF) was first identified in viruses. Early observations that global dysregulation of −1 PRF had deleterious effects on yeast cell growth suggested that −1 PRF may be used to control cellular gene expression, and the cell cycle in particular. Collection of sufficient numbers of viral −1 PRF signals coupled with advances in computer sciences enabled 2 complementary computational approaches to identify −1 PRF signals in free living organisms. The unexpected observation that almost all −1 PRF events on eukaryotic mRNAs direct ribosomes to premature termination codons engendered the hypothesis that −1 PRF signals post-transcriptionally regulate gene expression by functioning as mRNA destabilizing elements. Emerging research suggests that some human diseases are associated with global defects in −1 PRF. The recent discovery of −1 PRF signal-specific trans-acting regulators may provide insight into novel therapeutic strategies aimed at treating diseases caused by changes in gene expression patterns.