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Kiledjian Lab - Research

Research Interests*

Regulation of mRNA degradation is critical in maintaining normal gene expression and cellular homeostasis.  We are interested in understanding how cells control mRNA decay with an emphasis on a central step of mRNA decay involving removal of the 5' cap structure in a process termed decapping. We have identified three classes of decapping proteins:  (1) mRNA decapping (Wang et al,. 2002;  Song et al., 2010; Song et al., 2013)  (2) Cap structure scavenger decapping (Wang and Kiledjian 2001; Liu et al., 2002) and (3) quality control decapping of incompletely capped RNAs (Xiang et al., 2009; Jiao et al., 2010; Chang et al., 2012; Jiao et al., 2013). The two broad areas of research in the lab are:

I.  Determine the molecular mechanism underlying mRNA degradation

II. Characterize the regulatory role of mRNA decapping facors in human disorders

*Last Updated February 2014

mRNA Decapping

Dcp2 and Nudt16 are mRNA decapping enzymes that specifically remove the 5'-cap moiety from capped mRNAs to initiate the 5'-end mRNA decay pathway in eukaryotes (Wang et al. 2002; Song et al. 2010).  Surprisingly, both proteins appear to preferentially target specific mRNAs (Li et al., 2008; Li et al, 2009; Song et al. 2010; Li et al. 2011). Consistent with transcript specificity, we have identified at least six new potential decapping proteins in mammals (Song et al., 2013) suggesting a more complet array of decapping enzymes are involved in the regulation of mammalian mRNA decay. We are currently pursuing identification of the specific mRNA targets and strategies to control their expression by regulating decapping.

Dcp2 mRNA decapping in Innate Immunity:  Dcp2 selectively regulates the stability of a subset of innate immunity mRNAs and influences the cellular susceptibility to viral challenge (Li et al., 2012).  Studies are underway to delineate how Dcp2 can influence innate immunity and whether modulation of Dcp2 can be used enhance the innate immune response to pathogens.

Scavenger Decapping and Spinal Muscular Atrophy

DcpS functions to clear residual cap structure normally generated by the 3'-end mRNA decay pathway  (Liu et al., 2002).  Homozygous disruption of the DcpS gene is embryonic lethal in mice, indicating it fulfills a critical for development.  DcpS is also involved in a broad range of functions including:  5' to 3' exonuclease activity (Liu and Kiledjian, 2005; Sinturel et al., 2012); cap proximal pre-mRNA splicing (Shen et al., 2008); and is the cellular target 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 in Spinal Muscular Atrophy.

Cap Quality Control

Contrary to prior perceptions, our recent finding demonstrate that incompletely capped RNAs are normally generated in yeast and mammalian cells and identified a novel class of incompletely-capped decapping proteins Rai1, Dxo1 and DXO that clear incompletely capped mRNAs/pre-mRNAs in a novel cap quality control mechanism (Xiang et al., 2009; Jiao et al., 2010; Chang 2012; Jiao 2013).  Moreover, the DXO proteins also possess intrinsic decapping and 5’-3’ exoribonuclease activity to single handedly degrade an aberrantly capped RNA.  We are currently pursuing the mechanism by which these proteins function in quality control and their physiological consequence in cells.

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