Guo Lab: Research

 

Overview: microRNA Biogenesis

miRNAs are involved in nearly every aspect of development and cell physiology. Mis-regulation of some miRNAs has been demonstrated to play important roles in diseases such as cancer. miRNAs regulate the expression of many protein-coding genes by targeting their messenger RNAs (mRNAs) for degradation or translational repression. To become the ~22-nt mature functional forms, the primary transcripts of miRNAs (pri-miRNAs) need to be specifically recognized and cleaved by a series of dedicated cellular processing factors. In this sense, it is this series of processing machinery that determines which RNAs out of the large number of RNA molecules existing in both the nucleus and cytoplasm are processed into mature miRNA.

The first step of the miRNA processing pathway requires Drosha (a ribonuclease III family member) and DGCR8 (an RNA-binding protein), and is regulated by additional protein factors such as lin-28. We are interested in understanding how pri-miRNAs are specifically recognized by the processing machinery and how this processing step is regulated.

Research Topics

Structural biology of pri-miRNA processing

Structural information is indispensible in understanding molecular mechanisms governing the functions of macromolecular complexes. We are interested in determing the three dimensional structures of proteins and protein-RNA complexes involved in pri-miRNA processing using x-ray crystallography and other structural biology techniques.

 

 

 

A potential function of heme in pri-miRNA processing

We found that the essential pri-miRNA processing factor DGCR8 binds heme via interactions that have never been observed in other heme proteins.  Ferric heme activates the pri-miRNA processing activity of DGCR8 in vitro. We aim to understand how heme binds DGCR8 and regulates miRNA maturation by using x-ray crystallography, biochemistry and spectroscopic methods. This investigation offers an opportunity to explore the use of heme analogs in correcting abnormal pri-miRNA processing observed in diseases such as cancer and DiGeorge Syndrome.