R-loops highlight the nucleus in ALS - PubMed (original) (raw)

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R-loops highlight the nucleus in ALS

Jayesh S Salvi et al. Nucleus. 2015.

Abstract

Amyotrophic lateral sclerosis (ALS) is a severely debilitating neurodegenerative disease linked to mutations in various genes implicated in cytoplasmic RNA metabolism. Recent studies from genetic models have also helped reveal connections between various ALS-linked factors and RNA-DNA hybrid (R-loop) regulation. Here, we examine how such hybrid-regulatory processes are pointing to a key role for the nucleus in ALS. We also present a potential molecular mechanism in which hybrids may represent at least one of the long sought after missing links between different ALS genes. Our opinion is that RNA-DNA hybrids will play a key role in deciphering ALS and other human diseases.

Keywords: Amyotrophic lateral sclerosis (ALS); Ataxin2; C9ORF72; FUS; R-loop; RNA-DNA hybrid; SOD1; Senataxin; TDP43; genome instability; stress granules.

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Figures

Figure 1.

Figure 1.

R-loop regulatory factors. (A) RNA modulatory processes involving RNA binding, degradation, and export cooperate with RNA-DNA hybrid resolving/suppressing factors and G4DNA helicases to suppress R-loop accumulation. On the other hand, G4DNA stabilizing factors can promote R-loop accumulation. R-loop accumulation can lead to genome-destabilizing collisions with transcription and/or replication machinery. (B) Examples of yeast and human R-loop regulators that may or may not be linked to ALS pathobiology.

Figure 2.

Figure 2.

Putative feedback loop between R-loops and stress granules may connect various ALS genes at the molecular level. Mutations (μ) in ALS-linked factors can abrogate their ability to suppress R-loop formation and/or lead to their aberrant sequestration in RNA-processing foci such as cytoplasmic stress granules. Increased R-loop accumulation in turn leads to genomic instability and aberrant transcript accumulations, which in turn further promotes stress granule formation and the cycle continues. Motor neurons are predicted to be particularly sensitive to such a deleterious and vicious cycle.

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