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A journey through the microscopic ages of DNA replication

inventions * M. Cristina Cardoso (van der Aa 1851), leaps by Galileo (Galilei 1610), and Hooke (1665), it was not until Carl Zeiss started to mass-produce microscopes in 1847 that DNA observation started to

Heterochromatin and gene positioning: inside, outside, any side?

. 2 and all present and past members of the laboratory for their contributions over the years. The laboratory of M. Cristina Cardoso is supported by grants of the German Research Foundation (DFG) and

Altered spatio-temporal dynamics of RNase H2 complex assembly at replication and repair sites in Aicardi–Goutières syndrome

Ribonuclease H2 plays an essential role for genome stability as it removes ribonucleotides misincorporated into genomic DNA by replicative polymerases and resolves RNA/DNA hybrids. Biallelic mutations in the genes encoding the three RNase H2 subunits cause Aicardi–Goutières syndrome (AGS), an early-onset inflammatory encephalopathy that phenotypically overlaps with the autoimmune...

CBP and p300 acetylate PCNA to link its degradation with nucleotide excision repair synthesis

The proliferating cell nuclear antigen (PCNA) protein serves as a molecular platform recruiting and coordinating the activity of factors involved in multiple deoxyribonucleic acid (DNA) transactions. To avoid dangerous genome instability, it is necessary to prevent excessive retention of PCNA on chromatin. Although PCNA functions during DNA replication appear to be regulated by...

Targeted manipulation of heterochromatin rescues MeCP2 Rett mutants and re-establishes higher order chromatin organization

Heterochromatic regions represent a significant portion of the mammalian genome and have been implied in several important cellular processes, including cell division and genomic stability. However, its composition and dynamics remain largely unknown. To better understand how heterochromatin functions and how it is organized within the context of the cell nucleus, we have...

The histone variant H2A.Bbd is enriched at sites of DNA synthesis

Histone variants play an important role in shaping the mammalian epigenome and their aberrant expression is frequently observed in several types of cancer. However, the mechanisms that mediate their function and the composition of the variant-containing chromatin are still largely unknown. A proteomic interrogation of chromatin containing the different H2A variants macroH2A.1.2...

Direct Homo- and Hetero-Interactions of MeCP2 and MBD2

Epigenetic marks like methylation of cytosines at CpG dinucleotides are essential for mammalian development and play a major role in the regulation of gene expression and chromatin architecture. The methyl-cytosine binding domain (MBD) protein family recognizes and translates this methylation mark. We have recently shown that the level of MeCP2 and MBD2, two members of the MBD...

Recognition of 5-Hydroxymethylcytosine by the Uhrf1 SRA Domain

Recent discovery of 5-hydroxymethylcytosine (5hmC) in genomic DNA raises the question how this sixth base is recognized by cellular proteins. In contrast to the methyl-CpG binding domain (MBD) of MeCP2, we found that the SRA domain of Uhrf1, an essential factor in DNA maintenance methylation, binds 5hmC and 5-methylcytosine containing substrates with similar affinity. Based on...

MeCP2 Dependent Heterochromatin Reorganization during Neural Differentiation of a Novel Mecp2-Deficient Embryonic Stem Cell Reporter Line

The X-linked Mecp2 is a known interpreter of epigenetic information and mutated in Rett syndrome, a complex neurological disease. MeCP2 recruits HDAC complexes to chromatin thereby modulating gene expression and, importantly regulates higher order heterochromatin structure. To address the effects of MeCP2 deficiency on heterochromatin organization during neural differentiation...

A Role for MeCP2 in Switching Gene Activity via Chromatin Unfolding and HP1γ Displacement

Methyl-CpG-binding protein 2 (MeCP2) is generally considered to act as a transcriptional repressor, whereas recent studies suggest that MeCP2 is also involved in transcription activation. To gain insight into this dual function of MeCP2, we assessed the impact of MeCP2 on higher-order chromatin structure in living cells using mammalian cell systems harbouring a lactose operator...

Distribution of DNA replication proteins in Drosophila cells

Background DNA replication in higher eukaryotic cells is organized in discrete subnuclear sites called replication foci (RF). During the S phase, most replication proteins assemble at the RF by interacting with PCNA via a PCNA binding domain (PBD). This has been shown to occur for many mammalian replication proteins, but it is not known whether this mechanism is conserved in...

Histone hypoacetylation is required to maintain late replication timing of constitutive heterochromatin

The replication of the genome is a spatio-temporally highly organized process. Yet, its flexibility throughout development suggests that this process is not genetically regulated. However, the mechanisms and chromatin modifications controlling replication timing are still unclear. We made use of the prominent structure and defined heterochromatic landscape of pericentric regions...

Generation and Characterization of Rat and Mouse Monoclonal Antibodies Specific for MeCP2 and Their Use in X-Inactivation Studies

Methyl CpG binding protein 2 (MeCP2) binds DNA, and has a preference for methylated CpGs and, hence, in cells, it accumulates in heterochromatin. Even though it is expressed ubiquitously MeCP2 is particularly important during neuronal maturation. This is underscored by the fact that in Rett syndrome, a neurological disease, 80% of patients carry a mutation in the MECP2 gene...

MeCP2 Rett mutations affect large scale chromatin organization

Rett syndrome is a neurological, X chromosomal-linked disorder associated with mutations in the MECP2 gene. MeCP2 protein has been proposed to play a role in transcriptional regulation as well as in chromatin architecture. Since MeCP2 mutant cells exhibit surprisingly mild changes in gene expression, we have now explored the possibility that Rett mutations may affect the ability...

3D-Image analysis platform monitoring relocation of pluripotency genes during reprogramming

Nuclear organization of chromatin is an important level of genome regulation with positional changes of genes occurring during reprogramming. Inherent variability of biological specimens, wide variety of sample preparation and imaging conditions, though pose significant challenges to data analysis and comparison. Here, we describe the development of a computational image analysis...

Step-Wise Assembly, Maturation and Dynamic Behavior of the Human CENP-P/O/R/Q/U Kinetochore Sub-Complex

Kinetochores are multi-protein megadalton assemblies that are required for attachment of microtubules to centromeres and, in turn, the segregation of chromosomes in mitosis. Kinetochore assembly is a cell cycle regulated multi-step process. The initial step occurs during interphase and involves loading of the 15-subunit constitutive centromere associated complex (CCAN), which...

Differential recruitment of DNA Ligase I and III to DNA repair sites

DNA ligation is an essential step in DNA replication, repair and recombination. Mammalian cells contain three DNA Ligases that are not interchangeable although they use the same catalytic reaction mechanism. To compare the recruitment of the three eukaryotic DNA Ligases to repair sites in vivo we introduced DNA lesions in human cells by laser microirradiation. Time lapse...

Modulation of muscle contraction by a cell-permeable peptide

In contrast to immortal cell lines, primary cells are hardly susceptible to intracellular delivery methods such as transfection. In this study, we evaluated the direct delivery of several cell-permeable peptides under noninvasive conditions into living primary adult rat cardiomyocytes. We specifically monitored the functional effects of a cell-permeable peptide containing the 15...

PCNA acts as a stationary loading platform for transiently interacting Okazaki fragment maturation proteins

Cardoso 1 0 Department of Biology II, Ludwig Maximilians University of Munich , 82152 Planegg-Martinsried , Germany 1 Max Delbrueck Center for Molecular Medicine , 13125 Berlin , Germany In DNA

MeCP2 interacts with HP1 and modulates its heterochromatin association during myogenic differentiation

There is increasing evidence of crosstalk between epigenetic modifications such as histone and DNA methylation, recognized by HP1 and methyl CpG-binding proteins, respectively. We have previously shown that the level of methyl CpG-binding proteins increased dramatically during myogenesis leading to large-scale heterochromatin reorganization. In this work, we show that the level...