MicroRNAs (miRNAs) are a large class of noncoding regulatory RNAs. In animals miRNAs base-pair with the 3’ untranslated region (UTR) of their target mRNAs to target them for cleavage or translational repression. Repressed target mRNAs accumulate in cytoplasmic structures termed P-bodies, where some targets may be degraded. Other targets appear to be stable and can subsequently be re-expressed. In either case, target degradation or re-expression, the fate of the repressing miRNAs remains obscure and we do not know whether they are recycled or degraded. Similarly, while miRNA expression patterns have been observed to be very dynamic, nothing is known about a “clearance” mechanism that could remove miRNAs from a cell upon transition from one developmental state to another. As both miRNA under- and over-expression can cause developmental abnormalities and human diseases such as cancer can result. These observations indicate the need for faithful control of miRNA levels in the cell. Generally, the accumulation of any cellular RNA is regulated by balancing transcription and RNA degradation. But while we have gained considerable knowledge about miRNA biogenesis, we know nothing about miRNA turnover, let alone quality control or surveillance mechanisms. I propose to perform genetic and biochemical analyses to identify and characterize components of miRNA turnover/degradation machinery in C. elegans. By addressing the lifespan (half-life) and turn-over of miRNAs in vivo, this work has the potential to generate novel insights into normal development and disease, especially many forms of cancer that are often associated with deregulation of miRNAs. Ultimately the identified components can serve as spring-boards to venture into the mammalian systems and provide crucial insights for our understanding of miRNA function in animals.
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