Exosc2 deficiency leads to developmental disorders by causing a nucleotide pool imbalance in zebrafish

Yatsuka, Hiroyuki; Hada, Koji; Shiraishi, Hiroshi; Umeda, Ryohei; Morisaki, Ikuko; Urushibata, Hirotaro; Shimizu, Nobuyuki; Sebastian, Wulan Apridita; Hikida, Takatoshi; Ishitani, Tohru; Hanada, Reiko; Shimada, Tatsuo; Kimoto, Katsuhiko; Kubota, Toshiaki; Hanada, Toshikatsu

doi:10.1016/j.bbrc.2020.10.044

Cited by 10 publications

(13 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The EXOSC2-EXOSC4 and Rrp4-Rrp41 interfaces may be differentially impacted by the valine substitution in the two eukaryotic species which could account for the differences between budding yeast rrp4-G58V cells and homozygous EXOSC2-G30V patients. Previous studies also suggest that the RNA exosome plays an important role in tissue development and human embryonic stem cell differentiation (Belair et al 2019;Yatsuka et al 2020). The diverse clinical presentation in patients with SHRF could reflect these key developmental roles and/or different requirements in different cell types.…”

Section: Discussionmentioning

confidence: 97%

A budding yeast model for human disease mutations in the EXOSC2 cap subunit of the RNA exosome complex

Sterrett

Enyenihi

Leung

et al. 2021

RNA

View full text Add to dashboard Cite

RNA exosomopathies, a growing family of diseases, are linked to missense mutations in genes encoding structural subunits of the evolutionarily conserved, 10-subunit exoribonuclease complex, the RNA exosome. This complex consists of a 3-subunit cap, a 6-subunit, barrel-shaped, core and a catalytic base subunit. While a number of mutations in RNA exosome genes cause pontocerebellar hypoplasia, mutations in the cap subunit gene EXOSC2 cause an apparently distinct clinical presentation that has been defined as a novel syndrome SHRF (Short stature, Hearing loss, Retinitis pigmentosa and distinctive Facies). We generated the first in vivo model of the SHRF pathogenic amino acid substitutions using budding yeast by modeling pathogenic EXOSC2 missense mutations (p.Gly30Val and p.Gly198Asp) in the orthologous S. cerevisiae gene RRP4. The resulting rrp4 mutant cells show defects in cell growth and RNA exosome function. Consistent with altered RNA exosome function, we detect significant transcriptomic changes in both coding and non-coding RNAs in rrp4-G226D cells that model EXOSC2 p.Gly198Asp, suggesting defects in nuclear surveillance. Biochemical and genetic analyses suggest that the Rrp4 G226D variant subunit shows impaired interactions with key RNA exosome cofactors that modulate the function of the complex. These results provide the first in vivo evidence that pathogenic missense mutations present in EXOSC2 impair the function of the RNA exosome. This study also sets the stage to compare exosomopathy models to understand how defects in RNA exosome function underlie distinct pathologies.Words= 231

show abstract

Section: Discussionmentioning

confidence: 97%

A budding yeast model for human disease mutations in the EXOSC2 cap subunit of the RNA exosome complex

Sterrett

Enyenihi

Leung

et al. 2021

RNA

View full text Add to dashboard Cite

show abstract

“…Thus, the ski2 mutant may present a more severe deficiency in the salvage pathway that requires higher concentration of purine in the growth medium to achieve normal levels. A role in nucleotide homeostasis for RNA exosome-mediated RNA decay has also been proposed in animals 45 .…”

Section: Discussionmentioning

confidence: 99%

An active RNA transport mechanism into plant vacuoles

Floyd

Kazibwe

Morriss

et al. 2021

Preprint

View full text Add to dashboard Cite

RNA degradation inside the plant vacuole by the ribonuclease RNS2 is essential for maintaining nucleotide concentrations and cellular homeostasis via the nucleotide salvage pathway. However, the mechanisms by which RNA is transported into the vacuole are not well understood. While selective macroautophagy may contribute to this transport, macroautophagy-independent transport pathways also exist. Here we demonstrate a mechanism for direct RNA transport into vacuoles that is active in purified vacuoles and is ATP hydrolysis-dependent. We identify the RNA helicase SKI2 as a factor required for this transport pathway, as ski2 mutant vacuoles are defective in transport. ski2 mutants have an increased autophagy phenotype that can be rescued by exogenous addition of nucleosides, consistent with a function in nucleotide salvage. This newly-described transport mechanism is therefore critical for RNA degradation, recycling and cytoplasmic nucleotide homeostasis.

show abstract

“…Previous studies suggest the RNA exosome plays an important role in tissue development and human embryonic stem cell differentiation (B elair , S im et al . 2019; Y atsuka , H ada et al . 2020), which may be a pathway disrupted by these pathogenic amino acid substitutions that underlie SHRF pathology given the complexity of tissues affected.…”

Section: Discussionmentioning

confidence: 99%

A Budding Yeast Model for Human Disease Mutations in theEXOSC2Cap Subunit of the RNA Exosome

Sterrett

Enyenihi

Leung

et al. 2020

Preprint

View full text Add to dashboard Cite

RNA exosomopathies, a growing family of tissue-specific diseases, are linked to missense mutations in genes encoding the structural subunits of the conserved 10-subunit exoribonuclease complex, the RNA exosome. Such mutations in the cap subunit gene EXOSC2 cause the novel syndrome SHRF (Short stature, Hearing loss, Retinitis pigmentosa and distinctive Facies). In contrast, exosomopathy mutations in the cap subunit gene EXOSC3 cause pontocerebellar hypoplasia type 1b (PCH1b). Though having strikingly different disease pathologies, EXOSC2 and EXOSC3 exosomopathy mutations result in amino acid substitutions in similar, conserved domains of the cap subunits, suggesting that these exosomopathy mutations have distinct consequences for RNA exosome function. We generated the first in vivo model of the SHRF pathogenic amino acid substitutions using budding yeast by introducing the EXOSC2 mutations in the orthologous S. cerevisiae gene RRP4. The resulting rrp4 mutant cells have defects in cell growth and RNA exosome function. We detect significant transcriptomic changes in both coding and non-coding RNAs in the rrp4 variant, rrp4-G226D, which models EXOSC2 p.Gly198Asp. Comparing this rrp4-G226D mutant to the previously studied S. cerevisiae model of EXOSC3 PCH1b mutation, rrp40-W195R, reveals that these mutants have disparate effects on certain RNA targets, providing the first evidence for different mechanistic consequences of these exosomopathy mutations. Congruently, we detect specific negative genetic interactions between RNA exosome cofactor mutants and rrp4-G226D but not rrp40-W195R. These data provide insight into how SHRF mutations could alter the function of the RNA exosome and allow the first direct comparison of exosomopathy mutations that cause distinct pathologies.

show abstract

Exosc2 deficiency leads to developmental disorders by causing a nucleotide pool imbalance in zebrafish

Cited by 10 publications

References 31 publications

A budding yeast model for human disease mutations in the EXOSC2 cap subunit of the RNA exosome complex

A budding yeast model for human disease mutations in the EXOSC2 cap subunit of the RNA exosome complex

An active RNA transport mechanism into plant vacuoles

A Budding Yeast Model for Human Disease Mutations in theEXOSC2Cap Subunit of the RNA Exosome

Contact Info

Product

Resources

About