B.A. Rutgers University, Piscataway, NJ.
Ph.D. University of Pennsylvania, Philadelphia, PA
Postdoctoral Training: Gideon Dreyfuss, advisor. University of Pennsylvania, Philadelphia, PA
Postdoctoral Training: Stephen Liebhaber, advisor. University of Pennsylvania, Philadelphia, PA
Regulation of mRNA degradation is critical in maintaining normal gene expression and cellular homeostasis. Research in the Kiledjian lab is centered on the regulation of gene expression by the control of mRNA stability with an emphasis on the role of the 5´-end cap and its removal (decapping) in modulating mRNA turnover. Identification and characterization of critical components in the decapping pathway have enabled the lab to uncover (1) all known mammalian decapping enzymes (Wang et al,. 2002; Wang and Kiledjian 2001; Liu et al., 2002; Song et al., 2010; Song et al., 2013, Grudzien-Nogalska et al., 2016); (2) novel mRNA quality control mechanisms (Xiang et al., 2009; Jiao et al., 2010; Chang et al., 2012; Jiao et al., 2013); (3) new classes of 5´-end RNA caps (Jiao et al., 2017; Mauer et al., 2017); and (4) important links between mRNA decapping and human disorders (Singh et al., 2008; Li et al., 2012; Gogliotti et al., 2013; Ahmed et al., 2015; Castellanos-Rubio et al., 2016).
The Kiledjian lab has been at the forefront of identifying mammalian decapping enzymes, characterizing their functional significance in the modulation of gene expression, and their physiological significance in cells. These range from identification of Dcp2 as the first mRNA decapping enzyme to Nudt3 as the most recent and their respective roles in the regulation of innate immunity and cell migration. The lab is currently further exploring the functional role of these decapping enzymes as well as additional decapping enzymes in various cellular functions.
The lab also identified a distinct decapping protein, DcpS, that functions as a scavenger decapping enzyme in the 3´-end decay of RNA. DcpS is implicated in a range of functions including a cellular target for a potential drug candidate in the treatment of Spinal Muscular Atrophy as well as a mediator of human cognitive function where individuals with a disruption of DcpS decapping activity exhibit cognitive impairment. Using induced pluripotent stem cells (iPSCs) generated from individuals with homozygous disruption of the DcpS gene, the lab is currently focused on delineating the molecular mechanism by which DcpS decapping contributes to neural function and human cognition.
Novel 5´-end cap quality control.
The Kiledjian lab recently discovery a novel 5´ end capping quality control (CQC) mechanism in eukaryotic cells that degrades mRNAs with an incomplete 5´end. The significance of this finding is that it revealed mRNA capping, long thought to be a process that occurred to completion on all RNA polymerase II primary transcripts, is a modulated process. They showed that transcripts lacking a complete 5´ end cap can be generated in a regulated manner and further identified a novel class of non-canonical decapping enzymes they termed DXO family of proteins, that clear these aberrant caps. Collectively, these findings establish a new paradigm in post-transcriptional gene expression whereby addition of the 5´ cap is a regulated process and a heretofore unknown CQC mechanism exists to ensure the integrity of the cap through the DXO family of proteins. The molecular mechanism of CQC and its physiological consequence in cells are being pursued.
5´-end Nicotinamide Adenine Diphosphate (NAD+) cap in mammalian cells.
Another significant contribution from the Kiledjian lab is their demonstration that mammalian RNA can possess a 5´-end nicotinamide adenine diphosphate (NAD+) cap and appear to possess a novel NAD+ capping (NADding) mechanism. Moreover, the fungal and mammalian DXO proteins were shown to be potent “deNADding” enzymes that remove the NAD+ cap to facilitate RNA degradation. Importantly, contrary to the m7G cap that stabilizes mRNAs, the NAD+ cap promotes DXO-dependent rapid decay of an mRNA harboring this modification. Therefore, NAD serves as a 5´ tag to target an RNA for decay. These findings present a transformative mode of 5´ end epitranscriptomic RNA modification and a new modulatory network in the regulation of eukaryotic gene expression involving previously unforeseen caps.