Repeat Associated Non-ATG Translation Initiation: One DNA, Two Transcripts, Seven Reading Frames, Potentially Nine Toxic Entities!

Diseases associated with unstable repetitive elements in the DNA, RNA, and amino acids have consistently revealed scientific surprises. Most diseases are caused by expansions of trinucleotide repeats, which ultimately lead to diseases like Huntington's disease, myotonic dystrophy, fragile X syndrome, and a series of spinocerebellar ataxias. These repeat mutations are dynamic, changing through generations and within an individual, and the repeats can be bi-directionally transcribed. Unsuspected modes of pathogenesis involve aberrant loss of protein expression; aberrant overexpression of non-mutant proteins; toxic-gain-of-protein function through expanded polyglutamine tracts that are encoded by expanded CAG tracts; and RNA-toxic-gain-offunction caused by transcripts harboring expanded CUG, CAG, or CGG tracts. A recent advance reveals that RNA transcripts with expanded CAG repeats can be translated in the complete absence of a starting ATG, and this Repeat Associated Non-ATG translation (RAN-translation) occurs across expanded CAG repeats in all reading frames (CAG, AGC, and GCA) to produce homopolymeric proteins of long polyglutamine, polyserine, and polyalanine tracts. Expanded CTG tracts expressing CUG transcripts also show RAN-translation occurring in all three frames (CUG, UGC, and GCU), to produce polyleucine, polycysteine, and polyalanine. These RAN-translation products can be toxic. Thus, one unstable (CAG).(CTG) DNA can produce two expanded repeat transcripts and homopolymeric proteins with reading frames (the AUG-directed polyGln and six RAN-translation proteins), yielding a total of potentially nine toxic entities. The occurrence of RAN-translation in patient tissues expands our horizons of modes of disease pathogenesis. Moreover, since RAN-translation counters the canonical requirements of translation initiation, many new questions are now posed that must be addressed. This review covers RAN-translation and some of the pertinent questions.