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Published on: July 15, 2020
SRSF7 maintains its homeostasis through the expression of Split-ORFs and nuclear body assembly
Vanessa Königs1, Camila de Oliveira Freitas Machado1, Benjamin Arnold1
1Institute of Cell Biology and Neuroscience, Goethe University, Frankfurt am Main, Germany.
Abstract:
SRSF7 is an essential RNA-binding protein whose misexpression promotes cancer. Here, we describe how SRSF7 maintains its protein homeostasis in murine P19 cells using an intricate negative feedback mechanism. SRSF7 binding to its premessenger RNA promotes inclusion of a poison cassette exon and transcript degradation via nonsense-mediated decay (NMD). However, elevated SRSF7 levels inhibit NMD and promote translation of two protein halves, termed Split-ORFs, from the bicistronic SRSF7-PCE transcript. The first half acts as dominant-negative isoform suppressing poison cassette exon inclusion and instead promoting the retention of flanking introns containing repeated SRSF7 binding sites. Massive SRSF7 binding to these sites and its oligomerization promote the assembly of large nuclear bodies, which sequester SRSF7 transcripts at their transcription site, preventing their export and restoring normal SRSF7 protein levels. We further show that hundreds of human and mouse NMD targets, especially RNA-binding proteins, encode potential Split-ORFs, some of which are expressed under specific cellular conditions.
Insights
SRSF7 protein levels are regulated by a feedback loop involving nonsense-mediated decay (NMD). High SRSF7 inhibits NMD, allowing translation of protein halves that restore normal SRSF7 levels.
Area of Science:
- Molecular Biology
- Cell Biology
- RNA Biology
Background:
- SRSF7 is a crucial RNA-binding protein implicated in cancer development.
- Maintaining protein homeostasis is vital for cellular function and preventing disease.
Purpose of the Study:
- To elucidate the regulatory mechanism SRSF7 employs to maintain its own protein homeostasis.
- To investigate the role of nonsense-mediated decay (NMD) in SRSF7 regulation.
Main Methods:
- Analysis of SRSF7 pre-messenger RNA processing in murine P19 cells.
- Investigation of nonsense-mediated decay (NMD) pathway regulation.
- Identification and characterization of Split-ORFs in SRSF7 transcripts.
Main Results:
- SRSF7 binding to its pre-mRNA triggers a negative feedback loop involving NMD.
- Elevated SRSF7 inhibits NMD, leading to the translation of two protein halves (Split-ORFs).
- These protein halves suppress further SRSF7 expression by sequestering transcripts in nuclear bodies.
Conclusions:
- SRSF7 utilizes a sophisticated negative feedback mechanism involving NMD and Split-ORFs to maintain protein homeostasis.
- This regulatory system highlights a novel mechanism for controlling RNA-binding protein levels.
- The study identifies potential Split-ORFs in numerous NMD targets, suggesting broader biological relevance.
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