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The human genome encodes ~2000 microRNAs (miRNAs), which govern the expression of an estimated 1/3 of all human protein-coding mRNAs. Thereby miRNAs play a crucial role in the maintenance of cellular homeostasis and viability of living organisms. Conversely, dysregulated miRNAs have been implicated in various diseases such as cancer.

miRNAs silence expression of their target mRNAs either by degradation (decay) or by repressing their translation. While mRNA decay is terminal, translational repression is reversible and ideal for rapid response to environmental cues (e.g., stress, infection). Hence, the decision to degrade or translationally repress the mRNA could have great impacts on cellular homeostasis. However, a critical question remains to be answered: what mechanism determines whether a target mRNA is degraded or translationally repressed by a cognate miRNA?

We aim to delineate the molecular basis of this mechanism and determine why some miRNA:mRNA pairings trigger decay whereas others induce translational repression and discover the impact of disruption of this mechanism on cancer cells maintenance and drug-resistance. This discovery science project aims to unveil a fundamental biological mechanism. However, due to the pervasive roles of miRNAs, its outcomes will ultimately benefit research into numerous patho-physiological processes that are affected by miRNAs such as metabolism, immunity, and cancer, wherein rapid modulation of gene expression mediated by miRNAs is widespread.

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