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Book ; Audio / Video ; Thesis: Transkription und DNA-Reparatur in den Bruchpunktsregionen des MLL-Gens und seiner fünf häufigsten Translokationspartnergene AF4, AF9, AF10, ELL und ENL

Kowarz, Eric

2008

Author's details	von Eric Kowarz
Language	German
Size	1 CD-ROM, 12 cm
Publishing country	Germany
Document type	Book ; Audio / Video ; Thesis
Thesis / German Habilitation thesis	Frankfurt (Main), Univ., Diss., 2008
HBZ-ID	HT015628774
Database	Catalogue ZB MED Medicine, Health

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2008 MO 49	order for loan	Magazin

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Article ; Online: Model System to Analyze RNA-Mediated DNA Repair in Mammalian Cells.

Tschage, Lisa / Kowarz, Eric / Marschalek, Rolf

The CRISPR journal

2023 Volume 6, Issue 3, Page(s) 289–301

Abstract: RNA-templated/directed DNA repair" is a biological mechanism that has been experimentally demonstrated in bacteria, yeast, and mammalian cells. Recent study has shown that small noncoding RNAs (DDRNAs) and/or newly RNAPII transcribed RNAs (dilncRNAs) ... ...

Abstract	"RNA-templated/directed DNA repair" is a biological mechanism that has been experimentally demonstrated in bacteria, yeast, and mammalian cells. Recent study has shown that small noncoding RNAs (DDRNAs) and/or newly RNAPII transcribed RNAs (dilncRNAs) are orchestrating the initial steps of double-strand break (DSB) repair. In this study, we demonstrate that also pre-mRNA could be used as direct or indirect substrate for DSB repair. Our test system is based on (1) a stably integrated mutant reporter gene that produces constitutively a nonspliceable pre-mRNA, (2) a transiently expressed sgRNA-guided dCas13b::ADAR fusion protein to specifically RNA edit the nonspliceable pre-mRNA, and (3) transiently expressed
MeSH term(s)	Animals ; DNA Breaks, Double-Stranded ; RNA Precursors ; CRISPR-Cas Systems/genetics ; Gene Editing ; DNA Repair/genetics ; DNA/genetics ; RNA, Small Untranslated ; Mammals/genetics ; Mammals/metabolism
Chemical Substances	RNA Precursors ; DNA (9007-49-2) ; RNA, Small Untranslated
Language	English
Publishing date	2023-05-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3017891-5
ISSN	2573-1602 ; 2573-1599
ISSN (online)	2573-1602
ISSN	2573-1599
DOI	10.1089/crispr.2022.0105
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Zs.A 7195: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MG 119: Show issues

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Article ; Online: How chromosomal translocations arise to cause cancer: Gene proximity,

Streb, Patrick / Kowarz, Eric / Benz, Tamara / Reis, Jennifer / Marschalek, Rolf

iScience

2023 Volume 26, Issue 6, Page(s) 106900

Abstract: Chromosomal translocations (CTs) are a genetic hallmark of cancer. They could be identified as recurrent genetic aberrations in hemato-malignancies and solid tumors. More than 40% of all "cancer genes" were identified in recurrent CTs. Most of these CTs ... ...

Abstract	Chromosomal translocations (CTs) are a genetic hallmark of cancer. They could be identified as recurrent genetic aberrations in hemato-malignancies and solid tumors. More than 40% of all "cancer genes" were identified in recurrent CTs. Most of these CTs result in the production of oncofusion proteins of which many have been studied over the past decades. They influence signaling pathways and/or alter gene expression. However, a precise mechanism for how these CTs arise and occur in a nearly identical fashion in individuals remains to be elucidated. Here, we performed experiments that explain the onset of CTs: (1) proximity of genes able to produce prematurely terminated transcripts, which lead to the production of (2)
Language	English
Publishing date	2023-05-19
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2023.106900
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Article ; Online: How chromosomal translocations arise to cause cancer

Patrick Streb / Eric Kowarz / Tamara Benz / Jennifer Reis / Rolf Marschalek

iScience, Vol 26, Iss 6, Pp 106900- (2023)

Gene proximity, trans-splicing, and DNA end joining

2023

Abstract: Summary: Chromosomal translocations (CTs) are a genetic hallmark of cancer. They could be identified as recurrent genetic aberrations in hemato-malignancies and solid tumors. More than 40% of all “cancer genes” were identified in recurrent CTs. Most of ... ...

Abstract	Summary: Chromosomal translocations (CTs) are a genetic hallmark of cancer. They could be identified as recurrent genetic aberrations in hemato-malignancies and solid tumors. More than 40% of all “cancer genes” were identified in recurrent CTs. Most of these CTs result in the production of oncofusion proteins of which many have been studied over the past decades. They influence signaling pathways and/or alter gene expression. However, a precise mechanism for how these CTs arise and occur in a nearly identical fashion in individuals remains to be elucidated. Here, we performed experiments that explain the onset of CTs: (1) proximity of genes able to produce prematurely terminated transcripts, which lead to the production of (2) trans-spliced fusion RNAs, and finally, the induction of (3) DNA double-strand breaks which are subsequently repaired via EJ repair pathways. Under these conditions, balanced chromosomal translocations could be specifically induced. The implications of these findings will be discussed.
Keywords	Molecular biology ; Cell biology ; Functional aspects of cell biology ; Science ; Q
Language	English
Publishing date	2023-06-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: MLL-AF4 and a murinized pSer-variant thereof are turning on the nucleolar stress pathway.

Siemund, Anna Lena / Hanewald, Thomas / Kowarz, Eric / Marschalek, Rolf

Cell & bioscience

2022 Volume 12, Issue 1, Page(s) 47

Abstract: Background: Recent pathomolecular studies on the MLL-AF4 fusion protein revealed that the murinized version of MLL-AF4, the MLL-Af4 fusion protein, was able to induce leukemia when expressed in murine or human hematopoietic stem/progenitor cells (Lin et ...

Abstract	Background: Recent pathomolecular studies on the MLL-AF4 fusion protein revealed that the murinized version of MLL-AF4, the MLL-Af4 fusion protein, was able to induce leukemia when expressed in murine or human hematopoietic stem/progenitor cells (Lin et al. in Cancer Cell 30:737-749, 2016). In parallel, a group from Japan demonstrated that the pSer domain of the AF4 protein, as well as the pSer domain of the MLL-AF4 fusion is able to bind the Pol I transcription factor complex SL1 (Okuda et al. in Nat Commun 6:8869, 2015). Here, we investigated the human MLL-AF4 and a pSer-murinized version thereof for their functional properties in mammalian cells. Gene expression profiling studies were complemented by intracellular localization studies and functional experiments concerning their biological activities in the nucleolus. Results: Based on our results, we have to conclude that MLL-AF4 is predominantly localizing inside the nucleolus, thereby interfering with Pol I transcription and ribosome biogenesis. The murinized pSer-variant is localizing more to the nucleus, which may suggest a different biological behavior. Of note, AF4-MLL seems to cooperate at the molecular level with MLL-AF4 to steer target gene transcription, but not with the pSer-murinized version of it. Conclusion: This study provides new insights and a molecular explanation for the described differences between hMLL-hAF4 (not leukemogenic) and hMLL-mAf4 (leukemogenic). While the human pSer domain is able to efficiently recruit the SL1 transcription factor complex, the murine counterpart seems to be not. This has several consequences for our understanding of t(4;11) leukemia which is the most frequent leukemia in infants, childhood and adults suffering from MLL-r acute leukemia.
Language	English
Publishing date	2022-04-25
Publishing country	England
Document type	Journal Article
ZDB-ID	2593367-X
ISSN	2045-3701
ISSN	2045-3701
DOI	10.1186/s13578-022-00781-y
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Article ; Online: The role of reciprocal fusions in MLL-r acute leukemia: studying the chromosomal translocation t(6;11).

Kundu, Arpita / Kowarz, Eric / Marschalek, Rolf

Oncogene

2021 Volume 40, Issue 40, Page(s) 5902–5912

Abstract: Leukemia patients bearing t(6;11)(q27;q23) translocations can be divided in two subgroups: those with breakpoints in the major breakpoint cluster region of MLL (introns 9-10; associated mainly with AML M1/4/5), and others with breakpoints in the minor ... ...

Abstract	Leukemia patients bearing t(6;11)(q27;q23) translocations can be divided in two subgroups: those with breakpoints in the major breakpoint cluster region of MLL (introns 9-10; associated mainly with AML M1/4/5), and others with breakpoints in the minor breakpoint cluster region (introns 21-23), associated with T-ALL. We cloned all four of the resulting fusion genes (MLL-AF6, AF6-MLL, exMLL-AF6, AF6-shMLL) and subsequently transfected them to generate stable cell culture models. Their molecular function was tested by inducing gene expression for 48 h in a Doxycycline-dependent fashion. Here, we present our results upon differential gene expression (DGE) that were obtained by the "Massive Analyses of cDNA Ends" (MACE-Seq) technology, an established 3'-end based RNA-Seq method. Our results indicate that the PHD/BD domain, present in the AF6-MLL and the exMLL-AF6 fusion protein, is responsible for chromatin activation in a genome-wide fashion. This led to strong deregulation of transcriptional processes involving protein-coding genes, pseudogenes, non-annotated genes, and RNA genes, e.g., LincRNAs and microRNAs, respectively. While cooperation between the MLL-AF6 and AF6-MLL fusion proteins appears to be required for the above-mentioned effects, exMLL-AF6 is able to cause similar effects on its own. The exMLL-AF6/AF6-shMLL co-expressing cell line displayed the induction of a myeloid-specific and a T-cell specific gene signature, which may explain the T-ALL disease phenotype observed in patients with such breakpoints. This again demonstrated that MLL fusion proteins are instructive and allow to study their pathomolecular mechanisms.
MeSH term(s)	Gene Fusion/genetics ; Humans ; Leukemia, Myeloid, Acute/genetics ; Transfection ; Translocation, Genetic/genetics
Language	English
Publishing date	2021-08-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639046-8
ISSN	1476-5594 ; 0950-9232
ISSN (online)	1476-5594
ISSN	0950-9232
DOI	10.1038/s41388-021-01983-3
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Article ; Online: Image-Based Annotation of Chemogenomic Libraries for Phenotypic Screening.

Tjaden, Amelie / Chaikuad, Apirat / Kowarz, Eric / Marschalek, Rolf / Knapp, Stefan / Schröder, Martin / Müller, Susanne

Molecules (Basel, Switzerland)

2022 Volume 27, Issue 4

Abstract: Phenotypical screening is a widely used approach in drug discovery for the identification of small molecules with cellular activities. However, functional annotation of identified hits often poses a challenge. The development of small molecules with ... ...

Abstract	Phenotypical screening is a widely used approach in drug discovery for the identification of small molecules with cellular activities. However, functional annotation of identified hits often poses a challenge. The development of small molecules with narrow or exclusive target selectivity such as chemical probes and chemogenomic (CG) libraries, greatly diminishes this challenge, but non-specific effects caused by compound toxicity or interference with basic cellular functions still pose a problem to associate phenotypic readouts with molecular targets. Hence, each compound should ideally be comprehensively characterized regarding its effects on general cell functions. Here, we report an optimized live-cell multiplexed assay that classifies cells based on nuclear morphology, presenting an excellent indicator for cellular responses such as early apoptosis and necrosis. This basic readout in combination with the detection of other general cell damaging activities of small molecules such as changes in cytoskeletal morphology, cell cycle and mitochondrial health provides a comprehensive time-dependent characterization of the effect of small molecules on cellular health in a single experiment. The developed high-content assay offers multi-dimensional comprehensive characterization that can be used to delineate generic effects regarding cell functions and cell viability, allowing an assessment of compound suitability for subsequent detailed phenotypic and mechanistic studies.
MeSH term(s)	Cell Cycle/drug effects ; Cell Cycle/genetics ; Cell Line, Tumor ; Drug Discovery/methods ; Drug Evaluation, Preclinical/methods ; Genomics/methods ; High-Throughput Screening Assays/methods ; Humans ; Molecular Imaging/methods ; Reproducibility of Results ; Small Molecule Libraries ; Staining and Labeling
Chemical Substances	Small Molecule Libraries
Language	English
Publishing date	2022-02-21
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules27041439
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Article ; Online: MLL-AF4 and a murinized pSer-variant thereof are turning on the nucleolar stress pathway

Anna Lena Siemund / Thomas Hanewald / Eric Kowarz / Rolf Marschalek

Cell & Bioscience, Vol 12, Iss 1, Pp 1-

2022 Volume 15

Abstract: Abstract Background Recent pathomolecular studies on the MLL-AF4 fusion protein revealed that the murinized version of MLL-AF4, the MLL-Af4 fusion protein, was able to induce leukemia when expressed in murine or human hematopoietic stem/progenitor cells ( ...

Abstract	Abstract Background Recent pathomolecular studies on the MLL-AF4 fusion protein revealed that the murinized version of MLL-AF4, the MLL-Af4 fusion protein, was able to induce leukemia when expressed in murine or human hematopoietic stem/progenitor cells (Lin et al. in Cancer Cell 30:737–749, 2016). In parallel, a group from Japan demonstrated that the pSer domain of the AF4 protein, as well as the pSer domain of the MLL-AF4 fusion is able to bind the Pol I transcription factor complex SL1 (Okuda et al. in Nat Commun 6:8869, 2015). Here, we investigated the human MLL-AF4 and a pSer-murinized version thereof for their functional properties in mammalian cells. Gene expression profiling studies were complemented by intracellular localization studies and functional experiments concerning their biological activities in the nucleolus. Results Based on our results, we have to conclude that MLL-AF4 is predominantly localizing inside the nucleolus, thereby interfering with Pol I transcription and ribosome biogenesis. The murinized pSer-variant is localizing more to the nucleus, which may suggest a different biological behavior. Of note, AF4-MLL seems to cooperate at the molecular level with MLL-AF4 to steer target gene transcription, but not with the pSer-murinized version of it. Conclusion This study provides new insights and a molecular explanation for the described differences between hMLL-hAF4 (not leukemogenic) and hMLL-mAf4 (leukemogenic). While the human pSer domain is able to efficiently recruit the SL1 transcription factor complex, the murine counterpart seems to be not. This has several consequences for our understanding of t(4;11) leukemia which is the most frequent leukemia in infants, childhood and adults suffering from MLL-r acute leukemia.
Keywords	MLL-r acute leukemia ; MLL ; AF4 ; Fusion proteins ; pSer domain ; SL1 ; Biotechnology ; TP248.13-248.65 ; Biology (General) ; QH301-705.5 ; Biochemistry ; QD415-436
Subject code	572
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Book ; Online ; Thesis: The molecular principles of chromosomal translocations

Streb, Patrick [Verfasser] / Marschalek, Rolf [Akademischer Betreuer] / Kowarz, Eric [Akademischer Betreuer] / Marschalek, Rolf [Gutachter] / Fürst, Robert [Gutachter]

2023

Author's details	Patrick Streb ; Gutachter: Rolf Marschalek, Robert Fürst ; Rolf Marschalek, Eric Kowarz
Keywords	Biowissenschaften, Biologie ; Life Science, Biology
Subject code	sg570
Language	English
Publisher	Universitätsbibliothek Johann Christian Senckenberg
Publishing place	Frankfurt am Main
Document type	Book ; Online ; Thesis
Database	Digital theses on the web

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Article ; Online: Vaccine-induced COVID-19 mimicry syndrome.

Kowarz, Eric / Krutzke, Lea / Külp, Marius / Streb, Patrick / Larghero, Patrizia / Reis, Jennifer / Bracharz, Silvia / Engler, Tatjana / Kochanek, Stefan / Marschalek, Rolf

eLife

2022 Volume 11

Abstract: To fight the COVID-19 pandemic caused by the RNA virus SARS-CoV-2, a global vaccination campaign is in progress to achieve the immunization of billions of people mainly with adenoviral vector- or mRNA-based vaccines, all of which encode the SARS-CoV-2 ... ...

Abstract	To fight the COVID-19 pandemic caused by the RNA virus SARS-CoV-2, a global vaccination campaign is in progress to achieve the immunization of billions of people mainly with adenoviral vector- or mRNA-based vaccines, all of which encode the SARS-CoV-2 Spike protein. In some rare cases, cerebral venous sinus thromboses (CVST) have been reported as a severe side effect occurring 4-14 days after the first vaccination and were often accompanied by thrombocytopenia. Besides CVST, splanchnic vein thromboses (SVT) and other thromboembolic events have been observed. These events only occurred following vaccination with adenoviral vector-based vaccines but not following vaccination with mRNA-based vaccines. Meanwhile, scientists have proposed an immune-based pathomechanism and the condition has been coined vaccine-induced immune thrombotic thrombocytopenia (VITT). Here, we describe an unexpected mechanism that could explain thromboembolic events occurring with DNA-based but not with RNA-based vaccines. We show that DNA-encoded mRNA coding for Spike protein can be spliced in a way that the transmembrane anchor of Spike is lost, so that nearly full-length Spike is secreted from cells. Secreted Spike variants could potentially initiate severe side effects when binding to cells via the ACE2 receptor. Avoiding such splicing events should become part of a rational vaccine design to increase safety of prospective vaccines.
MeSH term(s)	COVID-19/prevention & control ; COVID-19 Vaccines/adverse effects ; ChAdOx1 nCoV-19/adverse effects ; Drug-Related Side Effects and Adverse Reactions/etiology ; Humans ; Pandemics ; SARS-CoV-2 ; Sinus Thrombosis, Intracranial/etiology ; Spike Glycoprotein, Coronavirus/genetics ; Spike Glycoprotein, Coronavirus/metabolism ; Syndrome ; Thrombocytopenia/etiology ; Vaccination/adverse effects ; Vaccines, DNA/adverse effects ; Venous Thrombosis/etiology
Chemical Substances	COVID-19 Vaccines ; Spike Glycoprotein, Coronavirus ; Vaccines, DNA ; spike protein, SARS-CoV-2 ; ChAdOx1 nCoV-19 (B5S3K2V0G8)
Language	English
Publishing date	2022-01-27
Publishing country	England
Document type	Journal Article
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.74974
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