RNA: Structure, Biophysics and Physiology

National Heart, Lung, And Blood Institute

Investigators

Linked publications & trials

Abstract

In the past year, we made advances in elucidating the regulatory role of G-quadruplex nucleic acids in biology. G-quadruplexes are unusually stable, four-stranded nucleic acid structures that are widely distributed in genomes and transcriptomes, and which have been proposed to play regulatory roles in transcription, translation and genome replication. In collaboration with the Wang and Myong laboratories at Johns Hopkins University, we demonstrated that the hexanucleotide repeat GGGGCC in the C9orf72 gene, whose expansion is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) forms a quadruplex, and that this helicase is resolved by the DEAH helicase DHX36. We demonstrated that DHX36 binds the hexanucleotide repeat with high affinity, and resolves it. This activity is necessary for driving the repeat-associated non-AUG (RAN) translation, which is the hallmark of ALS and FTD. These results can be recapitulated in vivo in pluripotent stem cells and differentiated motor neurons derived from ALS patients, and DHX36 is also aberrantly upregulated in tissues of ALS patients. Together, this suggests that the DHX36 interaction with the hexanucleotide repeat G-quadruplex is a potentially important molecular locus of intervention for therapeutic intervention in ALS and FTD.