Gene expression can be regulated at multiple levels including RNA stability. The rate of degradation of RNAs can vary by orders of magnitude and the stability of mRNAs can be regulated by cellular cues. Moreover, quality control pathways exist that target aberrant RNAs for rapid degradation. RNAs exist throughout their lifetime in dynamic ribonucleoprotein (RNP) complexes, which control the function and fate of the RNA. The mechanisms that control RNP dynamics are poorly understood. With the long-term goal of understanding the principles that underlie RNP modification and remodeling in RNA regulation, the specific objectives of this research is to understand, i) how mRNA decay activation by TTP is regulated during the inflammatory response, ii) the mechanisms by which the ATPase activity of the RNA helicase UPF1 is differentially regulated on target versus non-target mRNPs of the nonsense-mediated decay (NMD) pathway, iii) how the human decapping complex remodels to the translation initiation machinery to access the mRNA cap, iv) the role of arginine methylation and lysine acetylation in activation of decapping subsequent to deadenylation, and v) the role of 3' end tailing in snRNA metabolism. These questions will be addressed using combinations of biochemical, human cell-based, and global mass spec and sequencing assays. Pursuing these questions should reveal new principles of the role of RNP modification and remodeling in RNA regulation. Relevance to Public Health The control of RNA turnover is critical for proper regulation of gene expression, and its misregulation has been identified as a cause or consequence of multiple human disorders. The studies described here are aimed at understanding the mechanisms by which RNPs in human cells are modified and remodeled to control RNA function. This should provide fundamental new insights into mechanistic principles of mRNA regulation, which when deregulated can lead to disease. Specific links to diseases in this proposal include the study of mRNA regulation during inflammatory responses, critical for inhibiting inflammatory diseases, and the study of mutations in a deadenylase gene that have been linked to a childhood neurological disorder.
Correct regulation of gene expression is critical to human health. The regulation of protein- coding genes occurs at many levels, including at the level of messenger (m) RNA stability, the mis-regulation of which has been linked to multiple human disorders. mRNAs are coated with proteins to form mRNA-protein (mRNP) complexes, which control all aspects of mRNA function. In recent years it has become clear that modification and remodeling of mRNPs plays a central role in mRNA regulation. The objective of this proposal is to understand the general principles by which these processes control mRNA function, how this contributes to accurate gene regulation and how its mis-regulation is linked to disease.
