Nonsense-mediated mRNA decay uses complementary mechanisms to suppress mRNA and protein accumulation
Year: 2021
Type: article
Abstract: Nonsense-mediated mRNA decay (NMD) is an essential, highly conserved quality control pathway that detects and degrades mRNAs containing premature termination codons. Although the essentiality of NMD is frequently ascribed to its prevention of truncated protein accumulation, the extent to which NMD actually suppresses proteins encoded by NMD-sensitive transcripts is less well-understood than NMD-mediated suppression of mRNA. Here, we describe a reporter system that permits accurate quantification of both mRNA and protein levels via stable integration of paired reporters encoding NMD-sensitive and NMD-insensitive transcripts into the AAVS1 safe harbor loci in human cells. We use this system to demonstrate that NMD suppresses proteins encoded by NMD-sensitive transcripts by up to eightfold more than the mRNA itself. Our data indicate that NMD limits the accumulation of proteins encoded by NMD substrates by mechanisms beyond mRNA degradation, such that even when NMD-sensitive mRNAs escape destruction, their encoded proteins are still effectively suppressed.
Source: Life Science Alliance
Authors: Dylan B. Udy, Robert K. Bradley
Institutions: University of Washington, Fred Hutch Cancer Center
Language: English
Topic: RNA Research and Splicing
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,500
Awards: G1929525408, G4266498966, U2AF1 mutations in myelodysplastic syndromes: from mechanism to therapy, Training in Cellular and Molecular Biology, G5850682332, Interrogating the minor spliceosome to understand and treat leukemia, G887357334, G9000085113, Cancer Center Support Grant, Genetic and molecular basis for SRSF2 mutations in myelodysplasia, Functional and molecular consequences of SF3B1 mutations in human hematopoietic stem cells
OpenAlex ID: W4200536482