SRSF7 maintains its homeostasis through the expression of Split-ORFs and nuclear body assembly

• Published in: Nature structural & molecular biology Vol. 27; no. 3; pp. 260 - 273
• Main Authors: Königs, Vanessa, de Oliveira Freitas Machado, Camila, Arnold, Benjamin, Blümel, Nicole, Solovyeva, Anfisa, Löbbert, Sinah, Schafranek, Michal, Ruiz De Los Mozos, Igor, Wittig, Ilka, McNicoll, Francois, Schulz, Marcel H., Müller-McNicoll, Michaela
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.03.2020; Nature Publishing Group
• Subjects: 631/337/1645/2020; 631/45/612/1230; Amino Acid Sequence; Analysis; Animals; Assembly; Base Sequence; Binding Sites; Biochemistry; Biological Microscopy; Biomedical and Life Sciences; Cassettes; Cell Line, Tumor; Cell Nucleus - metabolism; Cell Nucleus - ultrastructure; Decay; Exons; Feedback; Gene expression; Gene Expression Regulation; Homeostasis; Homeostasis - genetics; Introns; Life Sciences; Membrane Biology; Mice; Mouse Embryonic Stem Cells - cytology; Mouse Embryonic Stem Cells - metabolism; Negative feedback; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Nonsense Mediated mRNA Decay; Oligomerization; Open Reading Frames; Poisons; Protein Binding; Protein Biosynthesis; Protein Structure; Protein transport; Proteins; Ribonucleic acid; RNA; RNA Precursors - genetics; RNA Precursors - metabolism; RNA transport; RNA-binding protein; RNA-Binding Proteins - classification; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Serine-Arginine Splicing Factors - genetics; Serine-Arginine Splicing Factors - metabolism; Transcription; Transcription, Genetic; Translation; Europe
• ISSN: 1545-9993; 1545-9985; 1545-9985
• DOI: 10.1038/s41594-020-0385-9

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. The RNA-binding protein SRSF7 autoregulates its protein levels through an intricate negative feedback mechanism that involves translation of two distinct protein halves, termed Split-ORFs; the potential to encode Split-ORFs is also seen in other targets of nonsense-mediated decay.