Lykke-Andersen, Jens - University of California, San Diego

个人简介

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.

研究领域

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: 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. 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. 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.

近期论文

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Dumdie JN, Cho K, Ramaiah M, Skarbrevik D, Mora-Castilla S, Stumpo DJ, Lykke-Andersen J, Laurent LC, Blackshear PJ, Wilkinson MF, Cook-Andersen H. (2018) Chromatin Modification and Global Transcriptional Silencing in the Oocyte Mediated by the mRNA Decay Activator ZFP36L2. Dev Cell. 44(3):392-402. Lardelli RM*, Schaffer AE*, Eggens VR*, Zaki MS, Grainger S, Sathe S, Van Nostrand EL, Schlachetzki Z, Rosti B, Akizu N, Scott E, Silhavy JL, Heckman LD, Rosti RO, Dikoglu E, Gregor A, Guemez-Gamboa A, Musaev D, Mande R, Widjaja A, Shaw TL, Markmiller S, Marin-Valencia I, Davies JH, de Meirleir L, Kayserili H, Altunoglu U, Freckmann ML, Warwick L, Chitayat D, Blaser S, Çağlayan AO, Bilguvar K, Per H, Fagerberg C, Christesen HT, Kibaek M, Aldinger KA, Manchester D, Matsumoto N, Muramatsu K, Saitsu H, Shiina M, Ogata K, Foulds N, Dobyns WB, Chi NC, Traver D, Spaccini L, Bova SM, Gabriel SB, Gunel M, Valente EM, Nassogne MC, Bennett EJ, Yeo GW, Baas F*, Lykke-Andersen J*, Gleeson JG*. (2017) Biallelic mutations in the 3' exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing. Nat Genet. 49(3):457-464. D'Lima NG, Ma J, Winkler L, Chu Q, Loh KH, Corpuz EO, Budnik BA, Lykke-Andersen J, Saghatelian A, Slavoff SA. (2017) A human microprotein that interacts with the mRNA decapping complex. Nat Chem Biol. 13(2):174-180. Martinez FJ, Pratt GA, Van Nostrand EL, Batra R, Huelga SC, Kapeli K, Freese P, Chun SJ, Ling K, Gelboin-Burkhart C, Fijany L, Wang HC, Nussbacher JK, Broski SM, Kim HJ, Lardelli R, Sundararaman B, Donohue JP, Javaherian A, Lykke-Andersen J, Finkbeiner S, Bennett CF, Ares M Jr, Burge CB, Taylor JP, Rigo F, Yeo GW. (2016) Protein-RNA Networks Regulated by Normal and ALS-Associated Mutant HNRNPA2B1 in the Nervous System. Neuron. 92(4):780-795. Durand S, Franks TM, Lykke-Andersen J. (2016) Hyperphosphorylation amplifies UPF1 activity to resolve stalls in nonsense-mediated mRNA decay. Nat Commun. 7:12434. Arribas-Layton M, Dennis J, Bennett EJ, Damgaard CK, Lykke-Andersen J. (2016) The C-Terminal RGG Domain of Human Lsm4 Promotes Processing Body Formation Stimulated by Arginine Dimethylation. Mol Cell Biol. 36(17):2226-35. Fu R, Olsen MT, Webb K, Bennett EJ, Lykke-Andersen J. (2016) Recruitment of the 4EHP-GYF2 cap-binding complex to tetraproline motifs of tristetraprolin promotes repression and degradation of mRNAs with AU-rich elements. RNA. 22(3):373-82. Wang Y, Arribas-Layton M, Chen Y, Lykke-Andersen J, Sen GL. (2015) DDX6 Orchestrates Mammalian Progenitor Function through the mRNA Degradation and Translation Pathways. Mol Cell. 60(1):118-30. Lee SR, Pratt GA, Martinez FJ, Yeo GW, Lykke-Andersen J. (2015) Target Discrimination in Nonsense-Mediated mRNA Decay Requires Upf1 ATPase Activity. Mol Cell. 59(3):413-25. Erickson SL, Corpuz EO, Maloy JP, Fillman C, Webb K, Bennett EJ, Lykke-Andersen J. (2015) Competition between Decapping Complex Formation and Ubiquitin-Mediated Proteasomal Degradation Controls Human Dcp2 Decapping Activity. Mol Cell Biol. 35(12):2144-53. Hausburg MA, Doles JD, Clement SL, Cadwallader AB, Hall MN, Blackshear PJ, Lykke-Andersen J, Olwin BB. (2015) Post-transcriptional regulation of satellite cell quiescence by TTP-mediated mRNA decay. Elife. 4:e03390. Toma KG, Rebbapragada I, Durand S, Lykke-Andersen J. (2015) Identification of elements in human long 3' UTRs that inhibit nonsense-mediated decay. RNA. 21(5):887-97. Reznik B, Clement SL, Lykke-Andersen J. (2014) hnRNP F complexes with tristetraprolin and stimulates ARE-mRNA decay. PLoS One. 9(6):e100992. Lykke-Andersen J, Bennett EJ. (2014) Protecting the proteome: Eukaryotic cotranslational quality control pathways. J Cell Biol. 204(4):467-76. Damgaard CK, Lykke-Andersen J. (2013) Regulation of ARE-mRNA Stability by Cellular Signaling: Implications for Human Cancer. Cancer Treat Res. 158:153-80. Lee SR, Lykke-Andersen J. (2013) Emerging roles for ribonucleoprotein modification and remodeling in controlling RNA fate. Trends Cell Biol. 23(10):504-10. Durand S, Lykke-Andersen J. (2013) Nonsense-mediated mRNA decay occurs during eIF4F-dependent translation in human cells. Nat Struct Mol Biol. 20(6):702-9. Arribas-Layton M, Wu D, Lykke-Andersen J, Song H. (2013) Structural and functional control of the eukaryotic mRNA decapping machinery. Biochim Biophys Acta. 1829(6-7):580-9. Brannan K, Kim H, Erickson B, Glover-Cutter K, Kim S, Fong N, Kiemele L, Hansen K, Davis R, Lykke-Andersen J, Bentley DL. (2012) mRNA decapping factors and the exonuclease Xrn2 function in widespread premature termination of RNA polymerase II transcription. Mol Cell. 46(3):311-24. Damgaard CK, Lykke-Andersen J. (2011) Translational coregulation of 5'TOP mRNAs by TIA-1 and TIAR. Genes Dev. 25(19):2057-68. 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.