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  • Laboratory of RNA Biology: Dziembowski Laboratory, ERA Chairs Research Group

Laboratory of RNA Biology: Dziembowski Laboratory, ERA Chairs Research Group

Andrzej Dziembowski, PhD, Professor adziembowski kolo

Correspondence address:
Laboratory of RNA Biology
International Institute of Molecular and Cell Biology in Warsaw
4 Ks. Trojdena Street, 02-109 Warsaw, Poland
Email: This email address is being protected from spambots. You need JavaScript enabled to view it.
www: www.iimcb.gov.pl & crisprmice.eu

Degrees:
2014 Professor of Biological Sciences, nomination by the President of the Republic of Poland
2009 DSc Habil in Molecular Biology, University of Warsaw, Poland
2002 PhD in Biology, cum laude, Department of Genetics Faculty of Biology, University of Warsaw, Poland
1998 MSC in Molecular Biology, University of Warsaw, Inter-Faculty Individual Studies in Mathematics and Natural Sciences, Poland

Professional Employment:
2019-present Professor, Head of the Laboratory of RNA Biology, IIMCB, Warsaw, Poland (100% appointment)
2011-present Associate Professor, Faculty of Biology, Department of Genetics and Biotechnology, University of Warsaw, Poland (currently 25% employment)
2014-2019 Full Professor, Institute of Biochemistry and Biophysics PAS, Poland
2010-2014 Associate Professor, Institute of Biochemistry and Biophysics PAS, Poland
2008-2010 Assistant Professor, Institute of Biochemistry and Biophysics PAS, Poland
2006-2011 Assistant Professor, Faculty of Biology, Department of Genetics and Biotechnology, University of Warsaw, Poland
2002 -2006 Post-doctoral fellow, Centre de Génétique Moléculaire, CNRS, France

Membership in Scientific Societies, Organizations and Panels:
2018-present EMBO Member
2004-present Member, RNA society

Fellowships and Awards:
2018 Foundation for Polish Science Prize for scientific achievements
2014 Foundation for Polish Science Master fellowship for scientific achievements
2013 Foundation for Polish Science Ideas for Poland Award
2013 Knight's Cross Order of Polonia Restituta for scientific achievements, President of Poland
2013 Jakub Karol Parnas Award for the best publication in biochemistry, Polish Biochemical Society
2013 National Science Centre Award for outstanding scientific achievements
2012 Member of the Academy of Young Scholars, Polish Academy of Sciences
2010 Prime Minister Award for the habilitation thesis
2009 Scholarship for outstanding young scientists, Minister of Science and Higher Education
2006 EMBO Installation Grant
2002 Postdoctoral fellowship, Foundation for Polish Science
2002 Prime Minister Award for PhD thesis
2001 Scholarship for Young Scientists, Foundation for Polish Science

finansowanie labu do zakładek FIN

Research focus

Posttranscriptional regulation of gene expression in metazoans

Gene expression in eukaryotes is regulated at multiple levels: starting from the chromatin structure, transcription, pre-mRNA processing, mRNA export from the nucleus, to mRNA stability and translation. The primary research interest of the laboratory is the regulation of gene expression at the posttranscriptional level. In the past, we were more interested in mechanistic aspects of the RNA metabolism, but now we are studying RNA biology at the organismal level using transgenic mouse lines as a main research model. 

Currently, our research is focused on two areas:
• Analysis of the function of processive ribonucleases, which through RNA degradation shape the transcriptomes of eukaryotic cells
• Analysis of cytoplasmic poly(A) and poly(U) polymerases which add nontemplated nucleotides to the 3’ ends of RNA molecules affecting their stability and biological functions

Analysis of the function of the processive ribonucleases

Processive exoribonucleases play a major role in eukaryotic RNA turnover and processing. Some act in the 3’-to-5’ direction, like the exosome complex or the monomeric ribonuclease DIS3l2. Alternatively, RNA molecules can be degraded or processed from the 5’ end by enzymes belonging to the XRN family of RNases. Importantly, the dysfunction of exoribonucleases is often connected to human diseases. Nuclear catalytic subunit of the exosome, DIS3 is one of the most frequently mutated genes in multiple myeloma (MM), a cancer of plasma cells. Mutations in DIS3L2 are associated with Perlman syndrome, a rare genetic overgrowth disease. Previously, we analyzed the mechanism of action and substrates of exoribonucleases using cellular model systems.

adziembowski exosome

Fig. 1: Exosome complexes in humans (Based on Tomecki et al EMBO J 2010; Lubas et al Mol Cell 2011, Lubas at al EMBO J 2013)

In the past, we identified catalytic subunits of a primary eucaryotic ribonuclease, the exosome both in yeast and humans (Dziembowski et al, NSMB 2007; Tomecki et al, EMBO J 2010) (Dziembowski et al, 2007; Tomecki et al, 2010). We have also shown that the complex, in addition to exonuclease activity, is also an endonuclease (Lebreton and Tomecki et al, Nature 2008) We participated in the biochemical and structural characterization of the exosome which together with the work of others allowed to elucidate the mechanism of its action (Drazkowska et al, NAR 2013; Hernandez et al, EMBO rep 2006; Lorentzen et al, Mol Cell 2008; Lorentzen et al, EMBO rep 2007; Malet et al, EMBO rep 2010). The exosome needs cofactors for its full activity, and we have described such complexes in human cells (Kalisiak et al, NAR 2017; Lubas et al, Cell rep 2015; Lubas et al, Mol Cell 2011). Moreover, we determined the nuclear exosome substrates which proved that this complex plays a primary role in shaping the human transcriptome, degrading variety of pervasive transcription products (Szczepinska et al, Genome res 2015) . Finally, since cancer genome projects revealed that the catalytic subunit of the exosome DIS3 is frequently mutated in multiple myeloma, we identified the vulnerabilities associated with such mutations to propose a novel drug target (Tomecki et al, NAR 2014).

In the future, we will investigate the functional interactions between RNA degrading enzymes and other cellular pathways involved in the expression of genetic information. In parallel, we will analyze the role of selected exoribonucleases using transgenic mouse models. Finally, we are very much interested in the role of mutations in DIS3 in the pathogenesis of multiple myeloma.

Analysis of cytoplasmic non-canonical poly(A) and poly(U) polymerases
Most mRNA molecules are polyadenylated during the classical 3’-end formation by canonical poly(A) polymerases. The poly(A) tail greatly enhances protein synthesis due to its interactions with poly(A) binding proteins (PABPs). PABPs not only protect the mRNA 3’ end from exoribonucleolytic decay but also directly interact with translation initiation factors promoting translation. It is now appreciated that poly(A) tail dynamics is more complex than previously suspected; deadenylated mRNAs in the cytoplasm can be degraded, uridylated or stored in a dormant state to be later re-adenylated to activate protein synthesis. The enzymes responsible for modifications of poly(A) tail are non-canonical poly(A) and poly(U) polymerases. The analysis of human cytoplasmic poly(U) polymerases TUT4/TUT7 led us to an unexpected discovery that uridylation is a potent restrictor of the retrotransposition of LINE-1 element, the only active autonomous transposon in humans (Warkocki et al. Cell 2018). Currently were are more focusing on cytoplasmic polyadenylation rathe than uridylation.

adziembowski model line1

Fig. 2: Model of Restriction of LINE-1 Retrotransposition by Uridylation (Based on Warkocki et al. Cell 2018)

Cytoplasmic polyadenylation was mostly studied in the context of gametogenesis and in neuronal synapses, where transcriptional activity is limited. Surprisingly, mouse lines devoid of the previously described cytoplasmic poly(A) polymerase GLD2 (TENT2) display no apparent phenotypes. We recently described a novel family of cytoplasmic poly(A) polymerases, TENT5 (FAM46), comprising four members in vertebrates – TENT5A-D. TENT5C acts as a tumor suppressor in multiple myeloma (Mroczek et al. Nature com 2017), while mutations in TENT5A lead to a rare genetic disease osteogenesis imperfecta. We have generated KO and knock-in (GFP/FLAG-tagged) mouse models for all TENT5 family members using CRISPR/Cas9 methodology. Although these genes are not essential, we detected a plethora of different phenotypes affecting several organs and biological processes. In the future, we aim to dissect the functions and mechanisms of cytoplasmic polyadenylation by TENT5 in the gametogenesis, innate immunity, hormonal regulation and neuronal physiology. We will use animal models combined with advanced transcriptomic and proteomic approaches. An important element of proposed studies is the refinement of methodology for genome-wide analysis of the global state of polyadenylation.

Other activities
Mus musculus is an organism of choice for functional studies relevant to human health. Surprisingly, there is currently no facility that would routinely generate mouse models by gene targeting approaches in Poland. During our work on TENT5 and DIS3 protein families, we began efforts to implement the CRISPR/Cas9 technology for the generation of transgenic mice. The method turned out to be extremely efficient in our hands, and within the past three years, we have obtained more than 20 different mouse lines with mutations in the locus (indels, point mutations, tags). This prompted us to establish a core facility (https://crisprmice.eu), which has the potential to foster the usage of new mouse models in biomedical research in Poland.

finansowanie labu do zakładek FIN

Lab Leader:dziembowski labmembers
Andrzej Dziembowski, PhD, Professor (starting 1st December 2019)

Senior Scientist:
Seweryn Mroczek, PhD (starting 1st December 2019; UW)

Postdoctoral Fellows:
Olga Gewartowska, PhD (starting 1st December 2019)
Anna Hojka-Osińska, PhD (starting 1st December 2019)
Paweł Krawczyk, PhD (starting 1st December 2019)
Tomasz Kuliński, MD PhD (starting 1st December 2019)
Monika Kusio-Kobiałka, PhD (starting 1st December 2019; UW)
Bartosz Tarkowski, PhD (starting 1st December 2019)

PhD Students:
Aleksandra Bilska, MSc (starting 1st December 2019; UW)
Michał Brouze, MSc (starting 1st December 2019)
Vladyslava Liudkovska, MSc (starting 1st December 2019)
Karolina Wróbel, MSc (starting 1st December 2019)

Graduate Student:
Jan Brancewicz, BSc (starting 1st December 2019)

Research Technicians:
Katarzyna Prokop, MSc (starting 1st December 2019)
Jakub Gruchota, MSc (starting 1st December 2019)
Marcin Szpila, Msc (starting 1st December 2019)

Laboratory Support Specialist:
Zofia Korbut-Mikołajczyk, MSc (starting 1st December 2019)

finansowanie labu do zakładek FIN