Gene expression can be regulated at multiple levels including mRNA degradation. The rate of degradation of mRNAs can vary by orders of magnitude and can be regulated by cellular cues, thus altering mRNA levels and thereby protein production in response to changes in cell conditions. mRNAs exist in cells in complex with proteins, forming the messenger ribonucleoproteins (mRNPs). The proteins of the mRNP complex control mRNA activity and protect the mRNA from decay. The targeting of an mRNA for degradation involves the recruitment of RNA degrading enzymes - however, the mechanism by which proteins of the mRNP are released to allow access for the mRNA decay enzymes to the mRNA is poorly understood. We have recently uncovered an activity dependent on ATP hydrolysis by the protein Upf1 that is critical for disassembling the mRNP to allow for degradation of mRNAs targeted to an mRNA decay pathway called nonsense-mediated decay (NMD). The objective of this research is to understand the importance and mechanism of mRNP remodeling and disassembly in various human mRNA decay pathways, through the following specific aims. First, it will be tested whether the ability to hyperphosphorylate Upf1, a central component of the NMD pathway that contains multiple phosphorylation sites for its kinase Smg1, serves as an mRNA decay amplifier in the NMD pathway that, via enhanced mRNA decay factor recruitment, enables NMD to compete with other mRNA decay pathways when mRNA decay factors are limiting. Second, it will be tested whether the ATPase activity of Upf1 is critical for remodeling of histone mRNPs to allow histone mRNA decay at the end of the cell cycle S-phase. Third, it will be tested whether ATPase activity of MOV10, a homolog of Upf1, is required for RNP remodeling during mRNA degradation activated by the RNA induced silencing complex (RISC) in complex with microRNAs. Relevance to Public Health Deregulation of mRNA turnover has been associated with a number of human disorders including cancers. The studies described here are aimed at elucidating fundamental mechanisms underlying the degradation of mRNA in human cells, which should provide insights into how mRNA decay is regulated under normal conditions and deregulated in human disorders.
The degradation of mRNA is an important point in regulation of gene expression and its mis- regulation is associated with multiple human disorders including cancers. Cellular mRNAs are coated with proteins in messenger ribonucleoprotein (mRNP) complexes, which control mRNA function and protect the mRNAs from degradation by mRNA decay enzymes. It has recently become clear that when an mRNA is targeted for decay, a critical and possibly regulated step is to strip the mRNP of associated proteins to allow access for mRNA decay enzymes. The goal of the studies of this proposal is to understand the mechanism by which various mRNA decay pathways achieve this.
|Durand, Sébastien; Franks, Tobias M; Lykke-Andersen, Jens (2016) Hyperphosphorylation amplifies UPF1 activity to resolve stalls in nonsense-mediated mRNA decay. Nat Commun 7:12434|
|Lee, Suzanne R; Pratt, Gabriel A; Martinez, Fernando J et al. (2015) Target Discrimination in Nonsense-Mediated mRNA Decay Requires Upf1 ATPase Activity. Mol Cell 59:413-25|
|Toma, Kalodiah G; Rebbapragada, Indrani; Durand, Sébastien et al. (2015) Identification of elements in human long 3' UTRs that inhibit nonsense-mediated decay. RNA 21:887-97|
|Lykke-Andersen, Jens; Bennett, Eric J (2014) Protecting the proteome: Eukaryotic cotranslational quality control pathways. J Cell Biol 204:467-76|
|Arribas-Layton, Marcos; Wu, Donghui; Lykke-Andersen, Jens et al. (2013) Structural and functional control of the eukaryotic mRNA decapping machinery. Biochim Biophys Acta 1829:580-9|
|Lee, Suzanne R; Lykke-Andersen, Jens (2013) Emerging roles for ribonucleoprotein modification and remodeling in controlling RNA fate. Trends Cell Biol 23:504-10|