Research
microRNAs
MicroRNAs (miRNAs) are a class of small non-coding RNAs with essential roles in gene expression. Together, miRNAs regulate the expression of >60% of genes and deficiencies in their maturation, as well as their levels within cells have been shown to drive several diseases including cancer. miRNAs are transcribed as longer transcripts (pri-miRNAs), the maturation of which requires the adequate RNA folding and the precise endonucleolytic cleavage of DROSHA and DICER1.
This processing is aided by more than 180 RNA-binding proteins. The resulting products are mature miRNAs that provide specificity to Argonaute (AGO), a key component in RNA silencing. Thus, the malfunction of components of the biogenesis pathway can result in various molecular phenotypes such as aberrant products, localization, or stability.
Research Interests:
Defects during miRNA biogenesis
My previous work and that of others has shown that dysregulation of RNA-binding proteins can promote miscleavage of miRNAs. These biogenesis defects lead to the production of aberrant miRNAs with altered target specificity. Comparison of miRNA miscleavage between normal and tumoral samples shows increased levels of aberrant miRNAs in tumors. Preliminary data analyzing patient’s mutations on DROSHA and DICER1 indicates that some can also generate aberrant miRNAs, suggesting the existence of multiple mechanisms of pathogenesis beyond the hotspot mutations on the catalytic domain.
Regulators of miRNA decay
The levels of mature miRNAs within cells are a function of their synthesis, maturation, and degradation. Decay of miRNAs is of particular interest since half-lives of miRNAs range between hours and days. For example, cardiac-specific miR-208 has a half-life of ~2 weeks, while others, such as miR-16 can decay within minutes in response to cell cycle phases or changes in light-darkness in retinal neurons. Despite these disparities in their stability, little is known about the mechanisms that regulate miRNA decay and how they impact on miRNA levels and therefore activity in cancer cells.