Poly-dipeptides encoded by the C9ORF72 repeats bind nucleoli, impede RNA biogenesis, and kill cells

By Ilmin Kwon, Siheng Xiang, Masato Kato, Leeju C. Wu, Pano Theodoropoulos, Tao Wang, Jiwoong Kim, Jonghyun Yun, Yang Xie, S. McKnight. Science, 2014

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Dipeptide repeat peptides on the attack Certain neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), are associated with expanded dipeptides translated from RNA transcripts of disease-associated genes (see the Perspective by West and Gitler). Kwon et al. show that the peptides encoded by the expanded repeats in the C9orf72 gene interfere with the way cells make RNA and kill cells. These effects may account for how this genetic form of ALS causes disease. Working in Drosophila, Mizielinska et al. aimed to distinguish between the effects of repeat-containing RNAs and the dipeptide repeat peptides that they encode. The findings provide evidence that dipeptide repeat proteins can cause toxicity directly. Science, this issue p. 1139 and p. 1192; see also p. 1118 Repeated structural motifs encoded by disease genes impair RNA metabolism and cause cell death. [Also see Perspective by West and Gitler] Many RNA regulatory proteins controlling pre–messenger RNA splicing contain serine:arginine (SR) repeats. Here, we found that these SR domains bound hydrogel droplets composed of fibrous polymers of the low-complexity domain of heterogeneous ribonucleoprotein A2 (hnRNPA2). Hydrogel binding was reversed upon phosphorylation of the SR domain by CDC2-like kinases 1 and 2 (CLK1/2). Mutated variants of the SR domains changing serine to glycine (SR-to-GR variants) also bound to hnRNPA2 hydrogels but were not affected by CLK1/2. When expressed in mammalian cells, these variants bound nucleoli. The translation products of the sense and antisense transcripts of the expansion repeats associated with the C9orf72 gene altered in neurodegenerative disease encode GRn and PRn repeat polypeptides. Both peptides bound to hnRNPA2 hydrogels independent of CLK1/2 activity. When applied to cultured cells, both peptides entered cells, migrated to the nucleus, bound nucleoli, and poisoned RNA biogenesis, which caused cell death.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/f0cebea5fe1db52f2c065e87e1e360eada702456

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Citations in the corpus

Physical Principles Underlying the Complex Biology of Intracellular Phase Transitions (2020, background): “In the context of low-complexity intrinsically disordered proteins, McKnight and coworkers (64, 75, 81, 82) identified stickers that drive the formation of cross-beta structures and enable the”
Protein Phase Separation: A New Phase in Cell Biology (2018, background): “Both the labile-to-stable gel [15] and liquid- to-solid [14, 16] transitions could explain the pathological conversion of SGs to aggregates in ALS [78], but their exact relation to both cellular SGs and aggregates remains undetermined.”
A Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation. (2015, positive): “Recent reports show that the prion-like LC domains of FUS can polymerize into fibrous amyloid-like assemblies in a cellfree system (Han et al., 2012; Kato et al., 2012; Kwon et al., 2013, 2014).”