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.
Current research questions in the lab include:
1) How are specific mRNAs targeted for rapid decay?
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.
2) How is translation and mRNA decay regulated by signaling?
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.
3) How do mRNA turnover pathways deal with the mRNP?
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.
Damgaard C.K. and Lykke-Andersen J. (2011) Translational co-regulation of 5’TOP mRNAs by TIA-1 and TIAR. Genes Dev. 25(19): In press.
Durand S. and Lykke-Andersen J. (2011) SnapShot: Nonsense-Mediated mRNA Decay. Cell. 145(2): 324. (Mini-Review).
Clement S.L., Scheckel C., Stoecklin G. and Lykke-Andersen J. (2011) Phosphorylation of Tristetraprolin by MK2 Impairs AU-Rich Element mRNA Decay by Preventing Deadenylase Recruitment. Mol Cell Biol. 31(2): 256-266.
Erickson S. and Lykke-Andersen J. (2011) Cytoplasmic mRNP granules at a glance. J. Cell Sci. 124: 293-297 (Review).
Franks T.M., Singh G. and Lykke-Andersen J. (2010) Upf1 ATPase-dependent mRNP disassembly is required for completion of nonsense-mediated mRNA decay. Cell. 143(6): 938-950.
Rebbapragada, I. and Lykke-Andersen, J. (2009) Execution of Nonsense-Mediated mRNA Decay: What Defines a Substrate? Curr. Opin. Cell Biol. 21: 394-402 (Review).
Singh, G., Rebbapragada, I., and Lykke-Andersen, J. (2008) A competition between stimulators and antagonists of Upf complex recruitment governs human nonsense-mediated mRNA decay. PLoS Biology 6(4): 860-871.
Franks, T. and Lykke-Andersen, J. (2008) The control of mRNA decapping and processing body formation. Molecular Cell. 32: 605-615 (Review).
Singh, G., Jakobs, S., Kleedehn, J., and Lykke-Andersen, J. (2007) Communication with the exon-junction complex and activation of nonsense-mediated decay by human Upf proteins occur in the cytoplasm. Molecular Cell. 27: 780-792.
Franks, T. and Lykke-Andersen, J. (2007) TTP and BRF proteins nucleate processing body formation to silence mRNAs with AU-rich elements. Genes Dev. 21: 719-735.
Wagner, E., Clement, S.L. and Lykke-Andersen, J. (2007) An unconventional human Ccr4-Caf1 deadenylase complex in nuclear cajal bodies. Mol. Cell. Biol. 27: 1686-1695.
Fenger-Gron, M., Fillman, C., Norrild, B. and Lykke-Andersen, J. (2005) Multiple human processing body factors and the ARE-binding protein TTP activate decapping. Molecular Cell 20: 905-915.
Lykke-Andersen, J. and Wagner, E. (2005) Recruitment and activation of mRNA decay enzymes by two ARE-mediated decay activation domains in the proteins TTP and BRF-1. Genes Dev. 19: 351-361.
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.