The Role of a Novel DNA-binding Protein WDHD1 in RNA Processing and Its Link to Diseases

Alternative splicing of pre-mRNA is a widespread process by which functionally diverse protein isoforms can be expressed according to different cellular programs. It is a powerful mechanism for expanding genomic versatility as well as proteomic complexity. Precision of intron removal is thus essential, and disruption of normal splicing patterns has been linked to various genetic diseases and cancers. Recent results from our lab have uncovered a potentially novel and important regulator of post-transcriptional RNA processing. Through proteomic and functional genomic approaches, we have found that WDHD1, a HMG domain-containing protein whose function is largely uncharacterized, stably associates with the spliceosome complexes and may be involved in controlling alternative splicing. We propose a set of synergistic experiments to further explore this function and, more importantly, its (patho)physiological relevance. First, we will establish a comprehensive profile of the pre-mRNA targets of WDHD1 via microarray analysis. Next, the exact molecular mechanism underlying WDHD1’s splicing function will be thoroughly dissected. Finally, physiological significance of WDHD1 can be illustrated by assessing tumorigenic and/or disease association of the splicing targets. By establishing the roles of WDHD1 in pre-mRNA splicing, these studies will expand our view on the post-transcriptional regulation of gene expression, and potentially open new avenues for therapeutic development.

Project ID:PG9901-0071
External Project ID:NHRI-EX99-9923SC