mRNA decay pre-complex assembly drives timely cell-state transitions during differentiation
Hideyuki Komori1, Geeta Rastogi1, John Paul Bugay2
1Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Abstract:
Complexes that control mRNA stability and translation promote timely cell-state transitions during differentiation by ensuring appropriate expression patterns of key developmental regulators. The Drosophila RNA-binding protein brain tumor (Brat) promotes the degradation of target transcripts during the maternal-to-zygotic transition in syncytial embryos and uncommitted intermediate neural progenitors (immature INPs). We identify ubiquitin-specific protease 5 (Usp5) as a candidate Brat interactor essential for the degradation of Brat target mRNAs. Usp5 promotes the formation of the Brat-deadenylase pre-complex in mitotic neural stem cells (neuroblasts) by facilitating Brat interactions with the scaffolding components of deadenylase complexes. The adaptor protein Miranda binds the RNA-binding domain of Brat, limiting its ability to bind target mRNAs in mitotic neuroblasts. Cortical displacement of Miranda activates Brat-deadenylase complex activity in immature INPs. We propose that the assembly of an enzymatically inactive and RNA-binding-deficient pre-complex poises mRNA degradation machineries for rapid activation, driving timely developmental transitions.
Insights
Ubiquitin-specific protease 5 (Usp5) interacts with the Drosophila RNA-binding protein Brat to regulate mRNA degradation. This interaction is crucial for timely cell-state transitions during development.
Area of Science:
- Developmental biology
- Molecular biology
- Genetics
Background:
- Cell-state transitions during differentiation rely on precise control of mRNA stability and translation.
- The Drosophila RNA-binding protein brain tumor (Brat) is known to degrade target transcripts in specific developmental stages.
Purpose of the Study:
- To identify novel interactors of Brat involved in mRNA degradation.
- To elucidate the mechanism by which Brat-mediated mRNA degradation is regulated during neural development.
Main Methods:
- Yeast three-hybrid screening to identify Brat interactors.
- Immunoprecipitation and Western blotting to confirm protein interactions.
- Analysis of mRNA levels and protein localization in Drosophila melanogaster.
Main Results:
- Ubiquitin-specific protease 5 (Usp5) was identified as a Brat interactor essential for target mRNA degradation.
- Usp5 facilitates the formation of the Brat-deadenylase pre-complex in neural stem cells.
- The adaptor protein Miranda regulates Brat activity by binding to its RNA-binding domain, with its displacement activating the complex in immature neural progenitors.
Conclusions:
- Usp5 plays a critical role in assembling the Brat-deadenylase complex, poised for activation.
- Regulation of Brat-deadenylase complex assembly and activity by Miranda is key to timely developmental transitions.
- This mechanism ensures precise control over gene expression during differentiation.
Related Concept Videos
02:31Nuclear Export of mRNA
02:27Nonsense-mediated mRNA Decay
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...
01:53RNA Stability
02:51mRNA Stability and Gene Expression
Cis-acting Elements involved in mRNA stability
02:53Ribosomal RNA Synthesis
Ribosome biogenesis begins with the synthesis of 5S and 45S pre-rRNAs by distinct RNA polymerases. The primary transcripts are extensively processed and modified before they are bound and folded by ribosomal proteins and assembly factors,...
02:41Chromatin Structure Regulates pre-mRNA Processing
The chromatin structure, especially...