المؤلفون: María Arroyo, Florian D. Hastert, Andreas Zhadan, Florian Schelter, Susanne Zimbelmann, Cathia Rausch, Anne K. Ludwig, Thomas Carell, M. Cristina Cardoso

المصدر: Nature Communications. 13

مصطلحات موضوعية: Multidisciplinary, Ubiquitin-Protein Ligases, Ubiquitination, General Physics and Astronomy, General Chemistry, DNA Methylation, Protein Serine-Threonine Kinases, General Biochemistry, Genetics and Molecular Biology, Dioxygenases, Mixed Function Oxygenases, DNA-Binding Proteins, Cytosine, Mice, Heterochromatin, Proto-Oncogene Proteins, 5-Methylcytosine, CCAAT-Enhancer-Binding Proteins, Animals, Humans, Protein Isoforms

الوصف: Oxidation of the epigenetic DNA mark 5-methylcytosine by Tet dioxygenases is an established route to diversify the epigenetic information, modulate gene expression and overall cellular (patho-)physiology. Here, we demonstrate that Tet1 and its short isoform Tet1s exhibit distinct nuclear localization during DNA replication resulting in aberrant cytosine modification levels in human and mouse cells. We show that Tet1 is tethered away from heterochromatin via its zinc finger domain, which is missing in Tet1s allowing its targeting to these regions. We find that Tet1s interacts with and is ubiquitinated by CRL4(VprBP). The ubiquitinated Tet1s is then recognized by Uhrf1 and recruited to late replicating heterochromatin. This leads to spreading of 5-methylcytosine oxidation to heterochromatin regions, LINE 1 activation and chromatin decondensation. In summary, we elucidate a dual regulation mechanism of Tet1, contributing to the understanding of how epigenetic information can be diversified by spatio-temporal directed Tet1 catalytic activity.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f8541957bfdcfb702d2528d6e67ffae9Test
https://doi.org/10.1038/s41467-022-32799-8Test

المؤلفون: Corella S. Casas-Delucchi, Christoph Engel, Patrick Weber, Julia L. Daiß, M. Cristina Cardoso, Gideon Coster, Peng Zhang, Cathia Rausch, Florian D. Hastert

المصدر: Nucleic Acids Research

مصطلحات موضوعية: DNA Replication, DNA polymerase, AcademicSubjects/SCI00010, DNA-Directed DNA Polymerase, Methylation, Genomic Instability, Cell Line, 03 medical and health sciences, chemistry.chemical_compound, Cytosine, Mice, 0302 clinical medicine, Genetics, Animals, Humans, Base Pairing, Molecular Biology, Cells, Cultured, In Situ Hybridization, Fluorescence, 030304 developmental biology, 0303 health sciences, Microscopy, Confocal, biology, Cell Cycle, DNA replication, DNA Helicases, Helicase, DNA, DNA-Directed RNA Polymerases, Chromatin, Cell biology, Histone, HEK293 Cells, chemistry, DNA methylation, biology.protein, 030217 neurology & neurosurgery

الوصف: DNA base modifications diversify the genome and are essential players in development. Yet, their influence on DNA physical properties and the ensuing effects on genome metabolism are poorly understood. Here, we focus on the interplay of cytosine modifications and DNA processes. We show by a combination of in vitro reactions with well-defined protein compositions and conditions, and in vivo experiments within the complex networks of the cell that cytosine methylation stabilizes the DNA helix, increasing its melting temperature and reducing DNA helicase and RNA/DNA polymerase speed. Oxidation of methylated cytosine, however, reverts the duplex stabilizing and genome metabolic effects to the level of unmodified cytosine. We detect this effect with DNA replication and transcription proteins originating from different species, ranging from prokaryotic and viral to the eukaryotic yeast and mammalian proteins. Accordingly, lack of cytosine methylation increases replication fork speed by enhancing DNA helicase unwinding speed in cells. We further validate that this cannot simply be explained by altered global DNA decondensation, changes in histone marks or chromatin structure and accessibility. We propose that the variegated deposition of cytosine modifications along the genome regulates DNA helix stability, thereby providing an elementary mechanism for local fine-tuning of DNA metabolism.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::02bf12a33fb379ce6209b4e91a18f1c4Test
https://pubmed.ncbi.nlm.nih.gov/34133727Test

المؤلفون: Anne Lehmkuhl, Ines Hellmann, Cathia Rausch, Florian D. Hastert, M. Cristina Cardoso, Peng Zhang, Anne K. Ludwig, Heinrich Leonhardt, Martha Smets

المصدر: Nucleus

مصطلحات موضوعية: 0301 basic medicine, Methyl-CpG-Binding Protein 2, Retrotransposon, Biology, MECP2, Cell Line, Mixed Function Oxygenases, 03 medical and health sciences, Mice, Rett syndrome, Proto-Oncogene Proteins, Animals, Humans, 5-hydroxymethylcytosine, Psychological repression, Methyl-CpG binding, Original Research, Genetics, DNA methylation, Cell Biology, DNA-binding domain, Methylation, repetitive elements, DNA-Binding Proteins, 030104 developmental biology, DNA Transposable Elements, genome stability, Binding domain

الوصف: One of the major functions of DNA methylation is the repression of transposable elements, such as the long-interspersed nuclear element 1 (L1). The underlying mechanism(s), however, are unclear. Here, we addressed how retrotransposon activation and mobilization are regulated by methyl-cytosine modifying ten-eleven-translocation (Tet) proteins and how this is modulated by methyl-CpG binding domain (MBD) proteins. We show that Tet1 activates both, endogenous and engineered L1 retrotransposons. Furthermore, we found that Mecp2 and Mbd2 repress Tet1-mediated activation of L1 by preventing 5hmC formation at the L1 promoter. Finally, we demonstrate that the methyl-CpG binding domain, as well as the adjacent non-sequence specific DNA binding domain of Mecp2 are each sufficient to mediate repression of Tet1-induced L1 mobilization. Our study reveals a mechanism how L1 elements get activated in the absence of Mecp2 and suggests that Tet1 may contribute to Mecp2/Mbd2-deficiency phenotypes, such as the Rett syndrome. We propose that the balance between methylation “reader” and “eraser/writer” controls L1 retrotransposition.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::62d147daec5c112bed9d5c413dd1b6d9Test
http://europepmc.org/articles/PMC5703239Test