Control of mRNA turnover plays an important role in determining levels of gene expression during cell growth, differentiation, and development. Aberrant mRNA turnover plays a critical role in the development of diseases including cancer and immune disorders, emphasizing the importance of stringent control of mRNA turnover. A major element responsible for rapid mRNA decay is the AU-rich element (ARE). Although they were found more than 15 years ago, the mechanism by which AREs dictate rapid mRNA decay is still unclear. The mechanistic steps of mRNA decay and the responsible enzymatic machinery in mammals are not completely elucidated. We purified and characterized the human exosome, a complex of ribonucleases, and demonstrated that it is required for rapid degradation of ARE-containing RNA substrates. The broad long-term goal of this work is to determine the mechanism of exosome-mediated mRNA decay with an emphasis on aspects that might be manipulated to target specific disease-related transcripts for degradation. To accomplish our long range goals, it is critical to understand the role of ARE-binding proteins (ARE-BPs) in the regulation of exosome-mediated mRNA degradation (specific aim 1).
This aim i nvolves the functional characterization of domains of KSRP, a novel ARE-BP that co-purifies with the exosome, that interact with the exosome and the ARE. In this aim, we will also test a strategy to target a specific mRNA for degradation which will provide information that might be later used as a therapeutic strategy. Understanding the role of exosome cofactors is also critical for elucidating the mechanism of exosome function in mRNA turnover and may ultimately provide a target for altering exosome activity (specific aim 2).
This aim i nvolves the identification and functional characterization of exosome cofactors in mRNA decay in vitro and in vivo. Finally, it is also necessary to demonstrate the mechanistic steps of mRNA decay and the effect of loss of exosome subunits on decay of unstable mRNAs with or without AREs in human cell lines (specific aim1). The proposed research should help elucidate the mechanisms by which mammalian mRNAs are degraded and provide targets for therapeutic intervention.
|Zheng, Yiming; Mennella, Vito; Marks, Steven et al. (2016) The Seckel syndrome and centrosomal protein Ninein localizes asymmetrically to stem cell centrosomes but is not required for normal development, behavior, or DNA damage response in Drosophila. Mol Biol Cell 27:1740-52|
|Chen, Jieyan V; Kao, Ling-Rong; Jana, Swadhin C et al. (2015) Rootletin organizes the ciliary rootlet to achieve neuron sensory function in Drosophila. J Cell Biol 211:435-53|
|Chou, Chu-Fang; Zhu, Xiaolin; Lin, Yi-Yu et al. (2015) KSRP is critical in governing hepatic lipid metabolism through controlling Per2 expression. J Lipid Res 56:227-40|
|Chou, Chu-Fang; Lin, Yi-Yu; Wang, Hsu-Kun et al. (2014) KSRP ablation enhances brown fat gene program in white adipose tissue through reduced miR-150 expression. Diabetes 63:2949-61|
|Lin, Yi-Yu; Chou, Chu-Fang; Giovarelli, Matteo et al. (2014) KSRP and MicroRNA 145 are negative regulators of lipolysis in white adipose tissue. Mol Cell Biol 34:2339-49|
|King, Peter H; Chen, Ching-Yi (2014) Role of KSRP in control of type I interferon and cytokine expression. J Interferon Cytokine Res 34:267-74|
|Chou, Chu-Fang; Lin, Wei-Jye; Lin, Chen-Chung et al. (2013) DEAD box protein DDX1 regulates cytoplasmic localization of KSRP. PLoS One 8:e73752|
|Li, Xuelin; Lin, Wei-Jye; Chen, Ching-Yi et al. (2012) KSRP: a checkpoint for inflammatory cytokine production in astrocytes. Glia 60:1773-84|
|Lin, Wei-Jye; Zheng, Xiaojia; Lin, Chen-Chung et al. (2011) Posttranscriptional control of type I interferon genes by KSRP in the innate immune response against viral infection. Mol Cell Biol 31:3196-207|
|Maitra, Sushmit; Chou, Chu-Fang; Luber, Christian A et al. (2008) The AU-rich element mRNA decay-promoting activity of BRF1 is regulated by mitogen-activated protein kinase-activated protein kinase 2. RNA 14:950-9|
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