TWO DIPEPTIDE REPEAT PROTEINS ARE PRODUCED FROM MAMMALIAN TELOMERIC RNA PREVIOUSLY THOUGHT TO BE a LONG NON-CODING RNA

Studies of neurological diseases caused by the expansion of nucleotide repeats led to the discovery that RNA can undergo translation by ribosomes in the absence of canonical AUG start signals, a process termed repeat-associated non-ATG translation (RAN). This discovery suggested that RNA transcribed from mammalian telomeres, termed TERRA, could generate RAN products. Indeed, two dipeptide repeat proteins can be produced: repeating arginine-valine (VR) and repeating glycine-leucine (GL). Both VR and GL form amyloid aggregates, and VR was observed to be expressed in cells with elevated TERRA, including a human osteosarcoma line. VR undergoes a change in aggregation state during mitosis, where it becomes dispersed, binds ribosomes, and can depress translation, possibly playing a regulatory role in the cell cycle. The discovery that RAN translation can occur on telomeric RNAs has opened new connections between telomeres, ageing, and the generation of RAN proteins with important biological activities.