“RAN Comes to RNA Translation”
Impactful discoveries induce initial chaos, revolt against established dogma, stimulate new questions, and significantly redirect the field of study. Dr. Laura Ranum and collegues (Department of Molecular Genetics and Microbiology) are to be congratulated on contributing an impactful report in their recent PNAS manuscript (PNAS 108:260 Jan. 2011). Through the description of repeat-associated non-ATG (RAN-) translation, they have indeed brought a bit of chaos and revolt to our understanding of protein expression. RAN-translation suggests that the well-established canonical rules of translation do not apply for CAG-CTG expansions. In the absence of ATG codons, which code for the traditional initiating methionine and thus sets the reading frame, expanded CAG and CTG trinucleotide repeats express homopolymeric expansion proteins in all three reading frames. Indeed, this discovery of RAN-translation raises the possibility that poly-Ala and poly-Ser proteins may contribute to the pathogenesis of at least some of the CAG poly-Gln diseases. Their data suggest that homopolymeric proteins may be invoved in the disease pathway previously thought to be mostly due to RNA gain-of-function. Importantly, they demonstrate in samples from spinocerebellar ataxia type-8 (SCA-8) disease, staining for Sca8GCA-Ala expansion protein was found in cerebellar Purkinge cells, while in myotonic dystrophy-1 disease, DM1CAG-Gln protein was present in heart, skeletal muscle, and myoblasts, thus confirming the presence of RAN-translation products in disease-relevant cells and tissues.
Ranum and colleagues, through their description of RAN-translation, have indeed ‘rocked our boat’ and have, in turn, opened many new questions. What is the mechanism of RAN-translation? While there is some indication of RNA structure (hairpin formation) being important for the initiation of RAN-translation, the control and tissue/cell specificity remain hard to imagine. Might RAN-translation occur at other trinucleotide repeats? Finally, and perhaps most importantly, are the homopolymeric proteins truly involved in trinucleotide repeat disease pathology?
The discovery of RAN-translation is now one of many recent revelations of the complex contributions by RNA (both non-coding and coding) to the control of gene expression that define a masterpiece of perfectly choreographed mayhem.
Steve P. Sugrue, Ph.D.
Senior Associate Dean for Research Affairs
College of Medicine