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Nonsense-mediated mRNA decay (NMD) is a post-transcriptional surveillance process that eliminates mRNAs containing premature termination codons (PTCs). NMD has been hypothesized to impact on several aspects of cellular function; however, its importance in the context of a mammalian organism has not been addressed in detail. Here we use mouse genetics to demonstrate that hematopoietic-specific deletion of Upf2, a core NMD factor, led to the rapid, complete, and lasting cell-autonomous extinction of all hematopoietic stem and progenitor populations. In contrast, more differentiated cells were only mildly affected in Upf2-null mice, suggesting that NMD is mainly essential for proliferating cells. Furthermore, we show that UPF2 loss resulted in the accumulation of nonproductive rearrangement by-products from the Tcrb locus and that this, as opposed to the general loss of NMD, was particularly detrimental to developing T-cells. At the molecular level, gene expression analysis showed that Upf2 deletion led to a profound skewing toward up-regulated mRNAs, highly enriched in transcripts derived from processed pseudogenes, and that NMD impacts on regulated alternative splicing events. Collectively, our data demonstrate a unique requirement of NMD for organismal survival.

Original publication

DOI

10.1101/gad.468808

Type

Journal article

Journal

Genes Dev

Publication Date

15/05/2008

Volume

22

Pages

1381 - 1396

Keywords

Animals, Base Sequence, Carrier Proteins, Cells, Cultured, Codon, Nonsense, Gene Expression Profiling, Gene Rearrangement, Hematopoietic Stem Cells, Humans, Lymphoid Progenitor Cells, Mice, Mice, Inbred C57BL, Mice, Transgenic, Models, Biological, Oligonucleotide Array Sequence Analysis, RNA Stability, Sequence Deletion