Andrzej Dziembowski

International Institute of Molecular and Cell Biology

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i-10 index

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Co-Authors

Paweł S. Krawczyk

International Institute of Molecular and Cell Biology

Rafał Tomecki

University of Warsaw

Seweryn Mroczek

International Institute of Molecular and Cell Biology

Dominik Cysewski

Institute of Biochemistry and Biophysics, Polish Academy of Sciences

Olga Gewartowska

International Institute of Molecular and Cell Biology

Tomasz M. Kuliński

International Institute of Molecular and Cell Biology

Roman J. Szczęsny

Institute of Biochemistry and Biophysics, Polish Academy of Sciences

Jakub Gruchota

International Institute of Molecular and Cell Biology

Aleksander Chlebowski

Roche (Switzerland)

Leszek Lipiński

Institute of Biochemistry and Biophysics, Polish Academy of Sciences

Cooperative Institutions

University of Warsaw

128

Polish Academy of Sciences

115

Institute of Biochemistry and Biophysics, Polish Academy of Sciences

107

International Institute of Molecular and Cell Biology

Centre National de la Recherche Scientifique

Instytut Biologii Doświadczalnej im. Marcelego Nenckiego

University of Oxford

Medical Research Council

Inserm

Institute of Bioorganic Chemistry, Polish Academy of Sciences

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Papers

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hUTP24 is essential for processing of the human rRNA precursor at site A₁, but not at site A₀

RNA Biology (2015)

Rafał Tomecki Anna Łabno Karolina Drążkowska Dominik Cysewski Andrzej Dziembowski

Production of ribosomes relies on more than 200 accessory factors to ensure the proper sequence of steps and faultless assembly of ribonucleoprotein machinery. Among trans-acting factors are numerous enzymes, including ribonucleases responsible for processing the large rRNA precursor synthesized by RNA polymerase I that encompasses sequences corresponding to mature 18S, 5.8S, and 25/28S rRNA. In humans, the identity of most enzymes responsible for individual processing steps, including endoribonucleases that cleave pre-rRNA at specific sites within regions flanking and separating mature rRNA, remains largely unknown. Here, we investigated the role of hUTP24 in rRNA maturation in human cells. hUTP24 is a human homolog of the Saccharomyces cerevisiae putative PIN domain-containing endoribonuclease Utp24 (yUtp24), which was suggested to participate in the U3 snoRNA-dependent processing of yeast pre-rRNA at sites A0, A1, and A2. We demonstrate that hUTP24 interacts to some extent with proteins homologous to the components of the yeast small subunit (SSU) processome. Moreover, mutation in the putative catalytic site of hUTP24 results in slowed growth of cells and reduced metabolic activity. These effects are associated with a defect in biogenesis of the 40S ribosomal subunit, which results from decreased amounts of 18S rRNA as a consequence of inaccurate pre-rRNA processing at the 5′-end of the 18S rRNA segment (site A1). Interestingly, and in contrast to yeast, site A0 located upstream of A1 is efficiently processed upon UTP24 dysfunction. Finally, hUTP24 inactivation leads to aberrant processing of 18S rRNA 2 nucleotides downstream of the normal A1 cleavage site.

Endoribonuclease

23S ribosomal RNA

Small nucleolar RNA

ribosome biogenesis

5.8S ribosomal RNA

P-site

10.1080/15476286.2015.1073437

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Citations (27)

Mistargeted mitochondrial proteins activate a proteostatic response in the cytosol

Nature (2015)

Lidia Wróbel Ulrike Topf Piotr Brągoszewski Sebastian Wiese Malgorzata E. Sztolsztener

Intermembrane space

Mitochondrial intermembrane space

Proteostasis

Cellular compartment

DNAJA3

Transport protein

10.1038/nature14951

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Citations (390)

DIS3L, cytoplasmic exosome catalytic subunit, is essential for development but not cell viability in mice

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Michał Brouze Marcin Szpila Areta M. Czerwińska Wiktor Antczak Seweryn Mroczek

Abstract Among numerous enzymes involved in RNA decay, processive exoribonucleases are the most prominent group responsible for the degradation of the entire RNA molecules. The role of mammalian cytoplasmic 3’-5’ exonuclease DIS3L at the organismal level remained unknown. Herein we established knock-in and knock-out mouse models to study DIS3L functions in mice. DIS3L is indeed a subunit of the cytoplasmic exosome complex, which disruption leads to severe embryo degeneration and death in mice soon after implantation. These changes could not be prevented by supplementing extraembryonic tissue with functional DIS3L through the construction of chimeric embryos. Preimplantation Dis3l -/- embryos were unaffected in their morphology and ability to produce functional embryonic stem cells showing that DIS3L is not essential for cell viability. There were also no major changes in the transcriptome level for both embryonic stem cells and blastocysts, as revealed by RNA sequencing experiments. Notably, however, DIS3L knock-out led to inhibition of the global protein synthesis. These results point to the essential role of DIS3L in mRNA quality control pathways crucial for proper protein synthesis during embryo development.

Exosome complex

Exosome

10.1101/2022.12.14.520403

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Citations (2)

Yeast nuclear PET127 gene can suppress deletions of the SUV3 or DSS1 genes: an indication of a functional interaction between 3' and 5' ends of mitochondrial mRNAs.

Acta Biochimica Polonica (1998)

Tomasz Węgierski Aleksandra Dmochowska A Jabłonowska Andrzej Dziembowski E Bartnik

Saccharomyces cerevisiae nuclear genes SUV3 and DSS1 encode putative RNA helicase and RNase II, respectively, which are subunits of the mitochondrial degradosome (mtEXO): a three-protein complex which has a 3' to 5' exoribonuclease activity and plays a major role in regulating stability of mitochondrial RNA. Lack of either of the two gene products results in a respiratory negative phenotype, while on the molecular level it causes a total block of mitochondrial translation, loss of the in vitro exoribonuclease activity and changes in stability and processing of many mtRNAs. We have found that the yeast nuclear gene PET127 present on a low or high copy number vector can effectively suppress the effects of the SUV3 or DSS1 gene disruptions. Since the product of the PET127 gene is involved in processing of the 5' ends of mitochondrial mRNAs, we suggest that there is a functional coupling between the 5' and 3' ends of mitochondrial mRNAs.

RNA Helicase A

Exoribonuclease

Nuclear gene

MT-RNR1

10.18388/abp.1998_4352

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Citations (19)

Cytoplasmic polyadenylation by TENT5A is required for proper bone formation

Cell Reports (2021)

Olga Gewartowska Goretti Aranaz Novaliches Paweł S. Krawczyk Seweryn Mroczek Monika Kusio-Kobiałka

Type I collagen

10.1016/j.celrep.2021.109015

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Citations (36)

TENT5 cytoplasmic noncanonical poly(A) polymerases regulate the innate immune response in animals

Science Advances (2022)

Vladyslava Liudkovska Paweł S. Krawczyk Aleksandra Brouze Natalia Gumińska Tomasz Węgierski

Innate immunity is the first line of host defense against pathogens. Here, through global transcriptome and proteome analyses, we uncover that newly described cytoplasmic poly(A) polymerase TENT-5 (terminal nucleotidyltransferase 5) enhances the expression of secreted innate immunity effector proteins in Caenorhabditis elegans . Direct RNA sequencing revealed that multiple mRNAs with signal peptide–encoding sequences have shorter poly(A) tails in tent-5 –deficient worms. Those mRNAs are translated at the endoplasmic reticulum where a fraction of TENT-5 is present, implying that they represent its direct substrates. Loss of tent-5 makes worms more susceptible to bacterial infection. Notably, the role of TENT-5 in innate immunity is evolutionarily conserved. Its orthologs, TENT5A and TENT5C, are expressed in macrophages and induced during their activation. Analysis of macrophages devoid of TENT5A/C revealed their role in the regulation of secreted proteins involved in defense response. In summary, our study reveals cytoplasmic polyadenylation to be a previously unknown component of the posttranscriptional regulation of innate immunity in animals.

Proteome

10.1126/sciadv.add9468

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Citations (14)

Mutation in mitochondrial chaperone TRAP1 results in male-specific autism

bioRxiv (Cold Spring Harbor Laboratory) (2023)

Małgorzata Rydzanicz Bożena Kuźniewska Marta Magnowska Tomasz Wójtowicz Ewa Borsuk

Abstract There is increasing evidence of mitochondrial dysfunction in autism spectrum disorders (ASD), but the causal relationships are unclear. In an ASD patient whose identical twin was unaffected, we identified a postzygotic mosaic mutation p.Q639* in the TRAP1 gene, which encodes a mitochondrial chaperone of the HSP90 family. Additional screening of 176 unrelated ASD probands revealed an identical TRAP1 variant in a male patient who had inherited it from a healthy mother. Notably, newly generated knock-in Trap1 p.Q641* mice display ASD-related behavioral abnormalities exclusively in males. Accordingly, Trap1 p.Q641* mutation also resulted in sex-specific changes in synaptic plasticity, number of presynaptic mitochondria, and metabolic substrate consumption. Thus, the TRAP1 p.Q639* mutation is the first example of a monogenic ASD caused by impaired mitochondrial protein homeostasis. One-Sentence Summary Patient mutation in TRAP1 causes autism in male mice.

Proband

Mitochondrial disease

Chaperone (clinical)

10.1101/2023.06.02.543381

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Citations (1)

Quantitative proteomics revealed C6orf203/MTRES1 as a factor preventing stress-induced transcription deficiency in human mitochondria

Nucleic Acids Research (2019)

Anna V. Kotrys Dominik Cysewski Sylwia D. Czarnomska Zbigniew Pietras Lukasz S. Borowski

Maintenance of mitochondrial gene expression is crucial for cellular homeostasis. Stress conditions may lead to a temporary reduction of mitochondrial genome copy number, raising the risk of insufficient expression of mitochondrial encoded genes. Little is known how compensatory mechanisms operate to maintain proper mitochondrial transcripts levels upon disturbed transcription and which proteins are involved in them. Here we performed a quantitative proteomic screen to search for proteins that sustain expression of mtDNA under stress conditions. Analysis of stress-induced changes of the human mitochondrial proteome led to the identification of several proteins with poorly defined functions among which we focused on C6orf203, which we named MTRES1 (Mitochondrial Transcription Rescue Factor 1). We found that the level of MTRES1 is elevated in cells under stress and we show that this upregulation of MTRES1 prevents mitochondrial transcript loss under perturbed mitochondrial gene expression. This protective effect depends on the RNA binding activity of MTRES1. Functional analysis revealed that MTRES1 associates with mitochondrial RNA polymerase POLRMT and acts by increasing mitochondrial transcription, without changing the stability of mitochondrial RNAs. We propose that MTRES1 is an example of a protein that protects the cell from mitochondrial RNA loss during stress.

DNAJA3

Transcription

Proteome

10.1093/nar/gkz542

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Citations (23)

Probabilistic Approach to Predicting Substrate Specificity of Methyltransferases

PLoS Computational Biology (2014)

Teresa Szczepińska Jan Kutner Michał Kopczyński Krzysztof Pawłowski Andrzej Dziembowski

We present a general probabilistic framework for predicting the substrate specificity of enzymes. We designed this approach to be easily applicable to different organisms and enzymes. Therefore, our predictive models do not rely on species-specific properties and use mostly sequence-derived data. Maximum Likelihood optimization is used to fine-tune model parameters and the Akaike Information Criterion is employed to overcome the issue of correlated variables. As a proof-of-principle, we apply our approach to predicting general substrate specificity of yeast methyltransferases (MTases). As input, we use several physico-chemical and biological properties of MTases: structural fold, isoelectric point, expression pattern and cellular localization. Our method accurately predicts whether a yeast MTase methylates a protein, RNA or another molecule. Among our experimentally tested predictions, 89% were confirmed, including the surprising prediction that YOR021C is the first known MTase with a SPOUT fold that methylates a substrate other than RNA (protein). Our approach not only allows for highly accurate prediction of functional specificity of MTases, but also provides insight into general rules governing MTase substrate specificity.

Akaike information criterion

10.1371/journal.pcbi.1003514

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Citations (40)

U6 RNAbiogenesis and disease association

Wiley Interdisciplinary Reviews - RNA (2013)

Seweryn Mroczek Andrzej Dziembowski

U6 snRNA is one of five uridine-rich noncoding RNAs that form the major spliceosome complex. Unlike other U-snRNAs, it reveals many distinctive aspects of biogenesis such as transcription by RNA polymerase III, transcript nuclear retention and particular features of transcript ends: monomethylated 5'-guanosine triphosphate as cap structure and a 2',3'-cyclic phosphate moiety (>P) at the 3' termini. U6-snRNA plays a central role in splicing and thus its transcription, maturation, snRNP formation, and recycling are essential for cellular homeostasis. U6 snRNA enters the splicing cycle as part of the tri-U4/U6.U5snRNP complex, and after significant structural arrangements forms the catalytic site of the spliceosome together with U2 snRNA and Prp8. U6 snRNA also contributes to the splicing reaction by coordinating metal cations required for catalysis. Many human diseases are associated with altered splicing processes. Disruptions of the basal splicing machinery can be lethal or lead to severe diseases such as spinal muscular atrophy, amyotrophic lateral sclerosis, or retinitis pigmentosa. Recent studies have identified a new U6 snRNA biogenesis factor Usb1, the absence of which leads to poikiloderma with neutropenia (PN) (OMIM 604173), an autosomal recessive skin disease. Usb1 is an evolutionarily conserved 3'→5' exoribonuclease that is responsible for removing 3'-terminal uridines from U6 snRNA transcripts, which leads to the formation of a 2',3' cyclic phosphate moiety (>P). This maturation step is fundamental for U6 snRNP assembly and recycling. Usb1 represents the first example of a direct association between a spliceosomal U6 snRNA biogenesis factor and human genetic disease.

Spliceosome

snRNP

Small nuclear RNA

Prp24

Exoribonuclease

Minor spliceosome

10.1002/wrna.1181

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Citations (44)