Our laboratory studies the mechanisms of regulation of translation and mRNA turnover in human gene expression. Research in recent years has revealed the importance of regulated mRNA translation and stability in the correct control of gene expression, and how its deregulation can lead to disease. Many of the general factors that direct mRNA translation and the enzymes that degrade mRNAs have been described in recent years. Our laboratory is interested in how these factors are differentially regulated on individual mRNAs to control their rates of translation and mRNA turnover, and how this is regulated by cell signaling.
The mechanisms by which specific mRNAs are targeted for rapid degradation remains poorly understood. We study the basic mechanisms that underlie the recognition and degradation of mRNAs targeted for various mRNA decay pathways, including the nonsense-mediated mRNA decay (NMD) pathway, an mRNA quality control pathway targeting aberrant mRNAs that fail to produce full-length protein, and the mRNA decay pathway that targets mRNAs containing AU-rich elements (AREs) in their 3’UTRs for rapid degradation.
The response of cells to changes in their environment often requires co-regulation of gene networks, but little is known about how this occurs at the post-transcriptional level. In two recent studies from the lab, we identified the stress granule-associated proteins TIA-1 and TIAR as key translational regulators in response to cell growth conditions of the network of 5’TOP mRNAs encoding protein biosynthesis factors (Damgaard and Lykke-Andersen, Genes&Dev, 2011), and we identified a mechanism by which an mRNA decay factor, TTP, which controls the degradation of mRNAs encoding cytokines, fails to recruit deadenylases to target mRNAs when TTP becomes phosphorylated in response to infection, thereby allowing cytokine production and an immune response (Clement et al., MCB, 2011). A current major focus of the lab is to understand the mechanisms by which signaling events modulate the activities of factors that control translation and degradation of regulated mRNA networks.
Just like our genomic DNA is coated in chromatin, mRNAs are coated with proteins in mRNPs. We recently observed that in the nonsense-mediated mRNA decay (NMD) pathway, failure of a central RNA helicase, called Upf1, to hydrolyze ATP causes the accumulation of partially degraded mRNP intermediates resistant to exonucleolytic decay (Franks et al., Cell, 2010). These observations suggest that active disassembly of the mRNP constitutes a critical step in mRNA turnover. Consistent with this idea, earlier observations primarily in yeast have shown that stalled ribosomes and strong RNA structure can act as obstacles to mRNA degradation, and that cap binding factors and poly-A binding protein can inhibit decapping and deadenylation, respectively. A current major focus of the laboratory is to understand the importance of ATPases/RNA helicases and of post-translational mRNP modifications in mRNA turnover, to learn whether mRNP remodeling is as critical to mRNA turnover as chromatin remodeling is to transcription.
Jens Lykke-Andersen received his Ph.D. from University of Copenhagen, Denmark in 1997. He was a postdoctoral fellow at Yale University Medical School before joining the faculty of MCD Biology at University of Colorado Boulder in 2001. He was named a Pew Scholar in 2003. He joined the Division of Biological Sciences at UCSD in 2009.