Are the processes of DNA replication and DNA repair reading a common structural chromatin unit?

Mamberti, Stefania; Cardoso, M. Cristina

doi:10.1080/19491034.2020.1744415

Cited by 11 publications

(10 citation statements)

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“…Chromatin loop structures are considered distinct units in the complex hierarchy of genome organization within the cell nucleus. At this level, individual loops may harbor the DNA elements that act as templates or regulators in different molecular processes (reviewed in ( 27 )). The most prominent examples are enhancer elements and promoters of genes that coordinate and regulate transcription via long ranging cis-interactions ( 94 , 125 , 126 ).…”

Section: Resultsmentioning

confidence: 99%

“…DNA halo analysis showed that these replicon sizes are in good agreement with measured sizes of chromatin loops. Hence, loop structures, potentially mediated by cohesins or functionally related proteins ( 25 , 26 ), represent the DNA element that defines replicons as functional unit in the DNA replication context (reviewed in ( 27 )). Labeling cells with modified nucleotides revealed that the replicon clusters observed on DNA fibers become visible as the before-mentioned replication foci in interphase nuclei ( 15 ).…”

Section: Introductionmentioning

confidence: 99%

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Developmental differences in genome replication program and origin activation

Rausch

Weber

Prorok

et al. 2020

Nucleic Acids Research

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To ensure error-free duplication of all (epi)genetic information once per cell cycle, DNA replication follows a cell type and developmental stage specific spatio-temporal program. Here, we analyze the spatio-temporal DNA replication progression in (un)differentiated mouse embryonic stem (mES) cells. Whereas telomeres replicate throughout S-phase, we observe mid S-phase replication of (peri)centromeric heterochromatin in mES cells, which switches to late S-phase replication upon differentiation. This replication timing reversal correlates with and depends on an increase in condensation and a decrease in acetylation of chromatin. We further find synchronous duplication of the Y chromosome, marking the end of S-phase, irrespectively of the pluripotency state. Using a combination of single-molecule and super-resolution microscopy, we measure molecular properties of the mES cell replicon, the number of replication foci active in parallel and their spatial clustering. We conclude that each replication nanofocus in mES cells corresponds to an individual replicon, with up to one quarter representing unidirectional forks. Furthermore, with molecular combing and genome-wide origin mapping analyses, we find that mES cells activate twice as many origins spaced at half the distance than somatic cells. Altogether, our results highlight fundamental developmental differences on progression of genome replication and origin activation in pluripotent cells.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Developmental differences in genome replication program and origin activation

Rausch

Weber

Prorok

et al. 2020

Nucleic Acids Research

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“…CTCF loops were shown to be highly dynamic, based on the very transient and cell cycle-dependent binding time of the protein, as measured by live-cell single-molecule microscopy [ 23 , 24 ]. However, as we reviewed recently [ 25 ], this dynamicity does not interfere with the concept of loops as stable structures over time. Their constant act of releasing and reforming will simply give rise to single-cell and cell cycle-dependent variability, which can be overcome by averaging the single-cell snapshots on a population level.…”

Section: Introductionmentioning

confidence: 84%

“…Through 3D structured illumination microscopy (3D-SIM), we could resolve the γH2AX foci into clusters of ~4 75-kb-sized nano-foci (median size) [ 31 ]. Interestingly, this DNA size corresponds to the one of a single chromatin loop (reviewed in [ 25 ]). We found that single γH2AX-labeled loops are clustered together by a couple of CTCF molecules at the anchor of this multi-loop domain [ 31 ].…”

Section: Introductionmentioning

confidence: 99%

The Chromatin Architectural Protein CTCF Is Critical for Cell Survival upon Irradiation-Induced DNA Damage

Mamberti

Pabba

Rapp

et al. 2022

IJMS

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CTCF is a nuclear protein initially discovered for its role in enhancer-promoter insulation. It has been shown to play a role in genome architecture and in fact, its DNA binding sites are enriched at the borders of chromatin domains. Recently, we showed that depletion of CTCF impairs the DNA damage response to ionizing radiation. To investigate the relationship between chromatin domains and DNA damage repair, we present here clonogenic survival assays in different cell lines upon CTCF knockdown and ionizing irradiation. The application of a wide range of ionizing irradiation doses (0–10 Gy) allowed us to investigate the survival response through a biophysical model that accounts for the double-strand breaks’ probability distribution onto chromatin domains. We demonstrate that the radiosensitivity of different cell lines is increased upon lowering the amount of the architectural protein. Our model shows that the deficiency in the DNA repair ability is related to the changes in the size of chromatin domains that occur when different amounts of CTCF are present in the nucleus.

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“…(Belton et al, 2012;Dekker et al, 2013;Dixon et al, 2012;Rowley and Corces, 2018;Yu and Ren, 2017). TADs are a distinctive feature of eukaryotic chromatin during interphase, and they are believed to play roles in the regulation of gene expression and, presumably, also DNA replication and repair (Luppino and Joyce, 2020;Mamberti and Cardoso, 2020;Matthews and Waxman, 2018;Noordermeer and Feil, 2020). TAD size varies in different organisms, and similar chromatin structures have been found in yeast (Eser et al, 2017).…”

Section: The Dual Role Of Cohesin In Sister Chromatid Cohesion and Interphase Chromatin Organizationmentioning

confidence: 99%

Hit the brakes – a new perspective on the loop extrusion mechanism of cohesin and other SMC complexes

Matityahu

Onn

2021

Journal of Cell Science

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The three-dimensional structure of chromatin is determined by the action of protein complexes of the structural maintenance of chromosome (SMC) family. Eukaryotic cells contain three SMC complexes, cohesin, condensin, and a complex of Smc5 and Smc6. Initially, cohesin was linked to sister chromatid cohesion, the process that ensures the fidelity of chromosome segregation in mitosis. In recent years, a second function in the organization of interphase chromatin into topologically associated domains has been determined, and loop extrusion has emerged as the leading mechanism of this process. Interestingly, fundamental mechanistic differences exist between mitotic tethering and loop extrusion. As distinct molecular switches that aim to suppress loop extrusion in different biological contexts have been identified, we hypothesize here that loop extrusion is the default biochemical activity of cohesin and that its suppression shifts cohesin into a tethering mode. With this model, we aim to provide an explanation for how loop extrusion and tethering can coexist in a single cohesin complex and also apply it to the other eukaryotic SMC complexes, describing both similarities and differences between them. Finally, we present model-derived molecular predictions that can be tested experimentally, thus offering a new perspective on the mechanisms by which SMC complexes shape the higher-order structure of chromatin.

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Are the processes of DNA replication and DNA repair reading a common structural chromatin unit?

Cited by 11 publications

References 91 publications

Developmental differences in genome replication program and origin activation

Developmental differences in genome replication program and origin activation

The Chromatin Architectural Protein CTCF Is Critical for Cell Survival upon Irradiation-Induced DNA Damage

Hit the brakes – a new perspective on the loop extrusion mechanism of cohesin and other SMC complexes

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