Abstract: Understanding The Role of Phosphorylation in the Nonsense-Mediated mRNA Decay (NMD) Pathway

One third of inherited human genetic diseases are caused by mRNAs harboring premature termination codons (PTCs) as a result of nonsense mutations. These aberrant transcripts are recognized and rapidly degraded by the nonsense-mediated mRNA decay (NMD) pathway. NMD is important, as it greatly reduces the synthesis of truncated proteins, some of which possess deleterious gain-of-function effects. Upf1p, Upf2p, and Upf3p are central NMD components. Upf1p and Upf2p are phosphorylated both in yeast and humans. Phosphorylation of the N-terminal region of Upf2p is crucial for its ability to elicit NMD and for its interaction with Hrp1p, another NMD component. Upf1p phosphorylation is necessary for NMD activity in worms and humans. We have identified eleven phosphorylation sites in yeast Upf1p using mass spectrometry, some of which are conserved in higher eukaryotes. Mutations in some of these conserved residues disrupt NMD activity. A better understanding of NMD may permit the discovery of approaches to modulate the stability and translation of aberrant mRNAs as a means to combat cancer and other human genetic disorders caused by nonsense mutations.
AVR is supported by the Amgen BioMINDS at UPR Program from the Amgen Foundation. This work is also supported by RISE Award 2R25GM61151, NIH U54 Award CA96297-03, NIH-NIGMS SCoRE Award GM008102-305, FIPI-UPR and grant P20 RR016174 from NCRR, a component of the NIH.

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