Regulation of Mammalian mRNA Degradation: Mechanism and Link to Human Disorders
Regulation of mRNA degradation is critical in maintaining normal gene expression as evident by disorders that arise as a consequence of aberrant mRNA decay. The life span of an individual mRNA represents a post-transcriptional opportunity for cells to influence the synthesis of nascent peptides. We are interested in understanding how cells control mRNA decay with an emphasis on modulating mRNA stability and gene expression in both normal and disease states. Our research focuses on two broad objectives:
- Determine the molecular mechanism underlying mRNA stabilization and degradation
- Characterize the regulatory role of mRNA degradation factors in specific neurological disorders including X-linked Mental Retardation and Spinal Muscular Atrophy.
The major ongoing research efforts in the lab are focused on a central step of mRNA decay involving removal of the 5’ cap structure in a process termed decapping. Decapping is carried out by at least two different proteins, the Dcp2 mRNA decapping enzyme (Wang, et al. 2002) and the DcpS scavenger decapping enzyme (Wang and Kiledjian 2001; Liu, et al. 2002).
mRNA Decapping: Dcp2 is an mRNA decapping enzyme that specifically removes the 5’-cap moiety from capped mRNAs and is important in initiating the 5’-end mRNA decay pathway in eukaryotes (Wang, et al., 2002). In addition to a general role of Dcp2 in decapping, its RNA-binding property (Piccirillo, et al., 2003) also confers selective regulation of a subset of mRNAs (Li, et al., 2008, 2009). We are currently pursuing experiments to identify the Dcp2 target mRNAs and devising strategies to control their expression.
An interesting link between mRNA decapping and cognitive function was recently revealed by our identification of a protein of previously unknown function implicated in X-linked Mental Retardation, VCX-A (Jiao, et al., 2006). We have shown VCX-A is an inhibitor of Dcp2 decapping and studies are underway to delineate how Dcp2 can modulate mRNA decapping in neuronal cells and how this could impact cognitive function.
We are also interested in deciphering the significance of decapping at the organismal level. We recently generated mice with a homozygous insertion of a ?-geo cassette within the Dcp2 gene. We are currently characterizing the functional consequence of the absence of Dcp2.
Scavenger Decapping: DcpS functions to clear the cell of the cap structure normally generated by the 3’ end mRNA decay pathway (Liu et al., 2002). DcpS is an essential gene as homozygous disruption of the DcpS gene is embryonic lethal in mice, indicating it fulfills a critical role(s) in an organism. In addition to a role in decapping, DcpS is also involved in a broad range of functions including: a positive feedback mechanism to enhance 5’ to 3’ exonuclease activity in yeast (Liu and Kiledjian, 2005); cap proximal pre-mRNA splicing in mammalian cells (Shen, et al., 2008); and is a target cellular substrate of a potential drug candidate for the treatment of spinal muscular atrophy (Singh, et al., 2008).
We are currently exploring the mechanism(s) by which DcpS exerts an influence on a diverse array of functions to further understand its molecular mechanism in the regulation of gene expression and explore its therapeutic potential.