•  chang108@as.edu.tw
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RESEARCH INTERESTS

RNA Metabolism Mediated by DExD/H-box RNA Helicases

Example of a Bypass Genetics ScreenWe have been studying the functions of the ubiquitous DExD/H-box proteins, which are often referred to as RNA helicases or RNA unwindases, in the budding yeast Saccharomyces cerevisiae and other organisms. These proteins are involved in essentially all RNA-related biological processes such as mRNA splicing, ribosomal biogenesis, mRNA export, translation, and RNA turnover. We have systematically examined the roles of a number of DExD/H-box proteins in yeast using a combination of genetic, molecular biological, biochemical, bioinformatic, and cell biological approaches. These studies allowed us to define the functions of Dbp3p (60S ribosomal subunit biogenesis), Dbp5p (mRNA export), Ded1p (translation initiation), Dhh1p (RNA turnover), and Prp28p (pre-mRNA splicing). Our study on Prp28p revealed that it controls the dissociation of U1 snRNP from the 5' splice site. This work bears significant ramifications and helps to usher in a notable paradigm shift in the field. It is now believed that the in vivo targets of DExD/H-box proteins are likely to be RNP complexes, rather than the RNA duplexes per se. Thus, DExD/H-box proteins function most likely as “RNPases” to “re-configure” various RNP complexes during and upon their transcriptional birth, their processing and export to cytoplasm for translation, and their ultimate demise by RNA turnover. In short, DExD/H-box proteins play key roles in governing the itinerary and functionality of the genetic information packages, from cradle to grave. Last, but not least, we are also exploring the possibility that one of the cellular DExD/H-box proteins is required for hepatitis C virus (HCV) replication. Studies of this DExD/H-box protein may provide a critical handle to understand how HCV replicates in the cell.

Genome-wide mRNA Splicing

By its nature and position in the gene expression pathway, splicing plays a key role in interpreting the embedded genomic information and does so under developmental and environmental influence. We have used splicing-specific microarrays to dissect how different processes, such as transcription, splicing, mRNA export, mRNA turnover, and translation, are coordinated.

A Genome-wide Bypass Genetics Screen for Yeast Essential Genes

Research done over the past few years in our lab has uncovered that a number of the so-called “essential” genes can in fact be eliminated, provided that specific “bypass” mutations are in place. Cloning the genes corresponding to the bypass mutations proved to yield rich and penetrating insights into the mechanistic role of the essential gene in question. We have therefore undertaken a systematic genome-wide screen for bypass mutations. Bypassing an essential gene is an extraordinary event and, as such, studies of bypass mutations virtually guarantee the discovery of novel and exciting biology. In this uncharted territory, we hope to uncover novel gene functions, genetic networks, as well as the underlying logic of genome evolution and organization.