A Defective mRNA Cleavage and Polyadenylation Complex Facilitates Expansions of Transcribed (GAA)n Repeats Associated with Friedreich’s Ataxia

• Published in: Cell reports (Cambridge) 2017-09, Vol.20 (10), p.2490-2500
• Main Authors: McGinty, Ryan J., Puleo, Franco, Aksenova, Anna Y., Hisey, Julia A., Shishkin, Alexander A., Pearson, Erika L., Wang, Eric T., Housman, David E., Moore, Claire, Mirkin, Sergei M.
• Format: Article
• Language: English
• Subjects: DNA double-strand breaks; DNA Replication - genetics; DNA Replication - physiology; Friedreich Ataxia - genetics; Friedreich Ataxia - metabolism; Friedreich’s ataxia; genetic screen; genome instability; Genomic Instability - genetics; Genomic Instability - physiology; Humans; Mutation - genetics; Point Mutation - genetics; Polyadenylation - genetics; Polyadenylation - physiology; repeat expansion; RNA polyadenylation; RNA processing; RNA, Messenger - genetics; trans-modifiers of repeat expansions; transcription-replication conflicts; Trinucleotide Repeat Expansion - genetics; Trinucleotide Repeat Expansion - physiology; Trinucleotide Repeats - genetics; whole-genome sequencing
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.08.051

Expansions of microsatellite repeats are responsible for numerous hereditary diseases in humans, including myotonic dystrophy and Friedreich’s ataxia. Whereas the length of an expandable repeat is the main factor determining disease inheritance, recent data point to genomic trans modifiers that can impact the likelihood of expansions and disease progression. Detection of these modifiers may lead to understanding and treating repeat expansion diseases. Here, we describe a method for the rapid, genome-wide identification of trans modifiers for repeat expansion in a yeast experimental system. Using this method, we found that missense mutations in the endoribonuclease subunit (Ysh1) of the mRNA cleavage and polyadenylation complex dramatically increase the rate of (GAA)n repeat expansions but only when they are actively transcribed. These expansions correlate with slower transcription elongation caused by the ysh1 mutation. These results reveal an interplay between RNA processing and repeat-mediated genome instability, confirming the validity of our approach. [Display omitted] •Genetic screen: UV mutagenesis → select for repeat expansions → genome sequencing•Point mutants in essential gene YSH1 increase the rate of GAA repeat expansions•YSH1 mutation → slow transcription elongation → DSB → repeat expansions McGinty et al. developed a genetic screen in S. cerevisiae to identify genes promoting expansions of (GAA)n repeats. The authors uncovered the unexpected involvement of essential RNA-processing gene, YSH1. Mutation in YSH1 leads to slow transcription elongation, promoting DSBs, whose repair via HR causes repeat expansions.