Regulation and functional effects of localized RNAs

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A large number of RNAs are not diffusely distributed in the cytoplasm, but are actively transported to various subcellular sites. After reaching their final destinations, localized RNAs are translated thus directing local protein production. While increasing numbers of localized RNA are being identified, the functional importance of these events is not well understood. We are focusing on a localization pathway that we have identified, which targets a number of RNAs to the tips of cellular protrusions. We have found that an important component of this pathway is the tumor-suppressor protein Adenomatous Polyposis Coli (APC) whose mutation is the initiating event in the progression of the majority of colorectal cancers. APC associates with RNAs at cellular protrusions in ribonucleoprotein complexes, which we term APC-RNPs. An additional component of APC-RNPs is the RNA-binding protein Fus/TLS, a protein whose mutation has been linked to both cancer and Amyotrophic Lateral Sclerosis. We have recently shown that ALS-associated mutants of Fus mislocalize APC-RNPs in internal cytoplasmic granules and misdirect their translation. We are using methods to isolate locally synthesized proteins and determine how RNA mislocalization and misdirection of translation affects protein properties and function. We are additionally addressing how these localized RNAs are affected and to what extent they contribute to colorectal cancer progression.