Witold Filipowicz
Witold Filipowicz
Mechanisms and regulation of microRNA function and metabolism in mammalian cells
Epigenetic control of gene expression and post-transcriptional silencing of genes by RNA interference (RNAi) and miRNAs have emerged recently as extraordinarily important and interesting areas of molecular biology. These reactions greatly contribute to the developmental and tissue specificity of gene expression, and also exemplify a key role of hundreds of novel non-coding RNAs in the regulation of gene expression. Our research is focused on mechanistic and regulatory aspects of miRNA function and miRNA metabolism in mammalian cells. miRNAs are ~21-nt RNAs involved in the regulation of development, differentiation, and many other fundamental processes; hundreds of different miRNAs are encoded in the genomes of metazoa. miRNAs generally imperfectly base-pair to the mRNA 3'-UTR and inhibit protein synthesis by either repressing mRNA translation or causing mRNA deadenylation and degradation.
miRNA-mediated regulation is a complex process involving many different proteins and intersecting with other cellular pathways. miRNAs function in the form of miRNPs (also known as miRISC), with Argonaute and GW182 proteins being the most important protein components. Biogenesis of miRNAs is also a complex reaction. It involves two enzymes of the RNase III family, Dicer and Drosha. In addition, many accessory factors regulate miRNA biosynthesis at different steps. miRNAs are generally assumed to have a very long half-life but our recent studies indicate that in some cells, in particular in neurons, miRNAs turn over very fast and that miRNA turnover is a subject of sophisticated regulation.
For more personal account of my scientific activity, see the “Reflections” article "Traversing the RNA World", published in J. Biol. Chem. (2017) 292: 8122-8133.
Filipowicz W. (2017) Traversing the RNA World
J Biol Chem 292:8122- 8135Krol J, Krol I, Alvarez CP, Fiscella M, Hierlemann A, Roska B, Filipowicz W. (2015) A network comprising short and long noncoding RNAs and RNA helicase controls mouse retina architecture
Nat Commun. 6:7305-17de la Mata M, Gaidatzis D, Vitanescu M, Stadler MB, Wentzel C, Scheiffele P, Filipowicz W, Grosshans H. (2015) Potent degradation of neuronal miRNAs induced by highly complementary targets
EMBO Rep. 16:500-11Ozgur S, Basquin J, Kamenska A, Filipowicz W, Standart N, Conti E. (2015) Structure of a Human 4E-T/DDX6/CNOT1 Complex Reveals the Different Interplay of DDX6-Binding Proteins with the CCR4-NOT Complex
Cell Rep. 13:703-11Mathys H, Basquin J, Ozgur S, Czarnocki-Cieciura M, Bonneau F, Aartse A,j Dziembowski A, Nowotny M, Conti E, and Filipowicz. (2014) Structural and biochemical insights into the role of the CCR4-NOT complex and DDX6 ATPase in microRNA-mediated repression
Mol Cell 54, 751-765Busskamp V, Krol J, Nelidova D, Daum J, Szikra T, Tsuda B, Jüttner J, Farrow K, Scherf BG, Alvarez CP, Genoud C, Sothilingam V, Tanimoto N, Stadler M, Seeliger M, Stoffel M, Filipowicz W, Roska B. (2014) miRNAs 182 and 183 are necessary to maintain adult cone photoreceptor outer segments and visual function
Neuron 83: 586-600Loedige I, Gaidatzis D, Sack R, Meister G, Filipowicz W. (2013) The mammalian TRIM-NHL protein TRIM71/LIN-41 is a repressor of mRNA function
Nucleic Acids Res. 41:518-32Doyle M, Badertscher L, Jaskiewicz L, Güttinger S, Jurado S, Hugenschmidt T, Kutay U, Filipowicz W. (2013) The double-stranded RNA binding domain of human Dicer functions as a nuclear localization signal
RNA 19(9):1238-52Bethune J, Artus-Revel C, and Filipowicz W. (2012) Kinetic analysis reveals successive steps leading to miRNA-mediated silencing in mammalian cells
EMBO Reports, 13:716-23.Krol J, Loedige I, Filipowicz W (2011) Regulation of miRNA Biogenesis, Function and Decay
Nat Rev Genet 11, 597-615Chekulaeva M, Mathys H, Zipprich JT, Attig J, Colic M, Parker R, Filipowicz W (2011) MicroRNA repression involves GW182-mediated recruitment of CCR4-NOT through conserved W-containing motifs
Nat Struct Mol Biol 18:1218-26Fabian MR, Sonenberg N, Filipowicz W (2010) Regulation of mRNA translation and stability by microRNAs
Annu Rev Biochem 79:351-79Krol J, Busskamp V, Markiewicz I, Stadler MB, Ribi S, Richter J, Duebel J, Bicker S, Fehling HJ, Schübeler D, Oertner TG, Schratt G, Bibel M, Roska B, Filipowicz W (2010) Characterization of microRNAs induced by light adaptation in mouse retina reveals rapid turnover as a common property of neuronal microRNA
Cell 141:618-31Fabian MR, Mathonnet G, Sundermeier T, Mathys H, Zipprich JT, Svitkin YV, Rivas F, Jinek M, Wohlschlegel J, Doudna JA, Chen CA, Shyu AB, Yates III JR, Hannon GJ, Filipowicz W, Duchaine TF, Sonenberg N (2009) Mammalian miRNA RISC recruits CAF1 and PABP to effect PABP-dependent deadenylation
Mol Cell 35:868-80Trabucchi M, Briata P, Garcia-Mayoral M, Haase AD, Filipowicz W, Ramos A, Gherzi R, Rosenfeld MG (2009) The RNA-binding protein KSRP Promotes the Biogenesis of a Subset of miRNAs
Nature 459:1010-1014Sarasin-Filipowicz M, Krol J, Markiewicz I, Heim M, Filipowicz W (2009) Decreased levels of microRNA miR-122 in hepatitis C patients with poor response to interferon therapy
Nature Med 15:31-33Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms of post-transcriptional regulation by microRNAs: Are the answers in sight?
Nature Rev Genet 9:102-114Sinkkonen L, Hugenschmidt T, Berninger P, Gaidatzis D, Mohn F, Artus-Revel C, Zavolan M, Svoboda P, Filipowicz W (2008) MicroRNAs control de novo DNA methylation through regulation of transcriptional repressors in mouse embryonic stem cells
Nature Struct Mol Biol 15:259-267Bhattacharyya S, Habermacher R, Martine U, Closs EI, Filipowicz W (2006) Relief of microRNA-mediated translational repression in human cells subjected to stress
Cell 125:1111-1124Pillai R, Bhattacharyya S, Artus C, Zoller T, Cougot N, Basyuk E, Bertrand E, Filipowicz W (2005) Inhibition of translational initiation by let-7 microRNA in human cells
Science 309:1573-1576Zhang H, Kolb FA, Jaskiewicz L, Westhof E, Filipowicz W (2004) Single processing center models for human Dicer and bacterial RNase III
Cell 118:57-68