mRNA decay is a key step in posttranscriptional gene regulation. The mechanisms by which mRNA degradation is regulated are still poorly understood. It has recently been observed that many proteins involved in mRNA degradation localize to cytoplasmic foci called processing bodes (PBs) and that mRNA degradation can take place there. Our efforts to identify proteins that localize to PBs have led to the discovery of a protein arginine methylation complex, called the methylosome, that interacts with PB components. The methylosome was previously shown to be involved in the cytoplasmic assembly of spliceosome components through its methylation of Sm proteins. Intriguingly, homologs of Sm proteins, called LSms, are components of PBs. I hypothesize that methylation of PB components may be important for the regulation of mRNA stability. The long-term goal of this project is to elucidate the function of the methylosome in mRNA degradation.
Specific Aim 1 will address whether PB proteins are methylated by the methylosome complex by testing if PB proteins are methylated, if PB proteins are demethylated, if PRMT5 is the methyltransferase responsible for PB protein methylation, and if the methylosome localizes to PBs.
Specific Aim 2 will address if PB function is dependent on the methylosome by testing if PB homeostasis dependeds on arginine methylation, if PB homeostasis is dependent on the methylosome, and if mRNA repression in PBs is dependent on methylation and the methylosome. Taken together, the experiments described in these aims will demonstrate if methylation in PBs is crucial for proper management of mRNA degradation, adding a previously unknown level of regulation to the control of mRNA stability. Abnormal control of mRNA stability has been implicated as the cause for several major human diseases, which have no known cure, such as cancer, arthritis, and Alzheimer's disease. Our lab studies mRNA degradation, which is a major regulatory component of mRNA stability. If the mechanisms that control mRNA degradation, such as the one described in this proposal, are elucidated this may lead to important insights into how to treat and cure these diseases.
|Arribas-Layton, Marcos; Dennis, Jaclyn; Bennett, Eric J et al. (2016) The C-Terminal RGG Domain of Human Lsm4 Promotes Processing Body Formation Stimulated by Arginine Dimethylation. Mol Cell Biol 36:2226-35|