Systematic generation and imaging of tandem repeats reveal base-pairing properties that promote RNA aggregation.

A common pathological feature of RNAs containing expanded repeat sequences is their propensity to aggregate in cells. While some repeat RNA aggregates have been shown to cause toxicity by sequestering RNA-binding proteins, the molecular mechanism of aggregation remains unclear. Here, we devised an efficient method to generate long tandem repeat DNAs and applied it to systematically determine the sequence features underlying RNA aggregation.

C9orf72 arginine-rich dipeptide repeats inhibit UPF1-mediated RNA decay via translational repression.

Expansion of an intronic (GGGGCC) repeat region within the C9orf72 gene is a main cause of familial amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). A hallmark of c9ALS/FTD is the accumulation of misprocessed RNAs, which are often targets of cellular RNA surveillance. Here, we show that RNA decay mechanisms involving upstream frameshift 1 (UPF1), including nonsense-mediated decay (NMD), are inhibited in c9ALS/FTD brains and in cultured cells expressing either of two arginine-rich dipeptide repeats (R-DPRs), poly(GR) and poly(PR).