RNA Surveillance Factor SMG5 Is Essential for Mouse Embryonic Stem Cell Differentiation

• Published in: Biomolecules (Basel, Switzerland) Vol. 14; no. 8; p. 1023
• Main Authors: Chen, Chengyan, Wei, Yanling, Jiang, Xiaoning, Li, Tangliang
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.08.2024; MDPI
• Subjects: Alternative splicing; Animals; c-MYC; c-Myc protein; Cell differentiation; Cell Differentiation - genetics; Cell viability; Clonal deletion; Cloning; Codons; differentiation; Embryo cells; Embryogenesis; Embryonic stem cells; Embryos; Enzymes; Ethylenediaminetetraacetic acid; Gene expression; Genes; Lethality; Messenger RNA; Mice; Mice, Knockout; mouse embryonic stem cells; Mouse Embryonic Stem Cells - cytology; Mouse Embryonic Stem Cells - metabolism; mRNA turnover; Myc protein; Neomycin; Nonsense Mediated mRNA Decay - genetics; Nonsense-mediated mRNA decay; Post-transcription; Protein biosynthesis; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; SMG5; Stem cells; Transcription termination; Transcriptomes; Tumorigenesis; China; Grand Island; United States > US; differentiation; mouse embryonic stem cells; nonsense-mediated mRNA decay; c-MYC; SMG5
• ISSN: 2218-273X; 2218-273X
• DOI: 10.3390/biom14081023

Nonsense-mediated mRNA decay (NMD) is a highly conserved post-transcriptional gene expression regulatory mechanism in eukaryotic cells. NMD eliminates aberrant mRNAs with premature termination codons to surveil transcriptome integrity. Furthermore, NMD fine-tunes gene expression by destabilizing RNAs with specific NMD features. Thus, by controlling the quality and quantity of the transcriptome, NMD plays a vital role in mammalian development, stress response, and tumorigenesis. Deficiencies of NMD factors result in early embryonic lethality, while the underlying mechanisms are poorly understood. SMG5 is a key NMD factor. In this study, we generated an conditional knockout mouse model and found that -null results in early embryonic lethality before E13.5. Furthermore, we produced multiple lines of knockout mouse embryonic stem cells (mESCs) and found that the deletion of in mESCs does not compromise cell viability. -null delays differentiation of mESCs. Mechanistically, our study reveals that the c-MYC protein, but not mRNA, is upregulated in SMG5-deficient mESCs. The overproduction of c-MYC protein could be caused by enhanced protein synthesis upon SMG5 loss. Furthermore, SMG5-null results in dysregulation of alternative splicing on multiple stem cell differentiation regulators. Overall, our findings underscore the importance of SMG5-NMD in regulating mESC cell-state transition.