Radial Organization in the Mammalian Nucleus

Crosetto, Nicola; Bienko, Magda

doi:10.3389/fgene.2020.00033

Cited by 37 publications

(36 citation statements)

References 133 publications

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“…Moreover, chromatin is hierarchically organized at multiple scale levels, which leads to the formation of structurally and functionally distinct chromatin domains [44][45][46][47], with which radiation interacts in a specific way and creates DNA lesions with different requirements for repair (reviewed in [48][49][50][51][52]). The chemical properties of the broken DNA ends were the first local factor ( Figure 1D) recognized to dramatically affect the ability of repair enzymes to rejoin DSBs [53].…”

Section: Global Versus Local Dsb Repair Pathway Selection and Regulationmentioning

confidence: 99%

A Paradigm Revolution or Just Better Resolution—Will Newly Emerging Superresolution Techniques Identify Chromatin Architecture as a Key Factor in Radiation-Induced DNA Damage and Repair Regulation?

Falk

Hausmann

2020

Cancers

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DNA double-strand breaks (DSBs) have been recognized as the most serious lesions in irradiated cells. While several biochemical pathways capable of repairing these lesions have been identified, the mechanisms by which cells select a specific pathway for activation at a given DSB site remain poorly understood. Our knowledge of DSB induction and repair has increased dramatically since the discovery of ionizing radiation-induced foci (IRIFs), initiating the possibility of spatiotemporally monitoring the assembly and disassembly of repair complexes in single cells. IRIF exploration revealed that all post-irradiation processes—DSB formation, repair and misrepair—are strongly dependent on the characteristics of DSB damage and the microarchitecture of the whole affected chromatin domain in addition to the cell status. The microscale features of IRIFs, such as their morphology, mobility, spatiotemporal distribution, and persistence kinetics, have been linked to repair mechanisms. However, the influence of various biochemical and structural factors and their specific combinations on IRIF architecture remains unknown, as does the hierarchy of these factors in the decision-making process for a particular repair mechanism at each individual DSB site. New insights into the relationship between the physical properties of the incident radiation, chromatin architecture, IRIF architecture, and DSB repair mechanisms and repair efficiency are expected from recent developments in optical superresolution microscopy (nanoscopy) techniques that have shifted our ability to analyze chromatin and IRIF architectures towards the nanoscale. In the present review, we discuss this relationship, attempt to correlate still rather isolated nanoscale studies with already better-understood aspects of DSB repair at the microscale, and consider whether newly emerging “correlated multiscale structuromics” can revolutionarily enhance our knowledge in this field.

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Section: Global Versus Local Dsb Repair Pathway Selection and Regulationmentioning

confidence: 99%

A Paradigm Revolution or Just Better Resolution—Will Newly Emerging Superresolution Techniques Identify Chromatin Architecture as a Key Factor in Radiation-Induced DNA Damage and Repair Regulation?

Falk

Hausmann

2020

Cancers

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“…The current view of higher-order chromatin organization depicts chromatin as distributed throughout the entire nuclear volume 7 . So far, most of the studies describing 3D chromatin organization were conducted either on cultured cells, or on cells in fixed tissue preparations 3,8,19,21,35 . To study 3D chromatin organization under physiological conditions in a live organism, we have developed a setup to visualize nuclei and chromatin in live, intact Drosophila larva.…”

Section: Live Imaging Of 3d Chromatin Distribution In Intact Drosophimentioning

confidence: 99%

“…Chromatin organization can change in space and time in a physiological, adaptive manner, where nuclear morphology is an important contributor that reflects the balance between cytoplasmic forces acting on the nucleus and the collective mechanical resistance of the lamina and the chromatin [20][21][22][23] . Additionally, nuclear morphology and chromatin organization can be altered due to experimental methodologies such as reduction in cell and nucleus volume due to fixation, change in osmolality, or as a result of culture on surfaces of various stiffness conditions [24][25][26] .…”

Section: Introductionmentioning

confidence: 99%

Live imaging of chromatin distribution in muscle nuclei reveals novel principles of nuclear architecture and chromatin compartmentalization

Pavlov¹,

Lorber²,

Bajpai³

et al. 2020

Preprint

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Packaging of the chromatin within the nucleus serves as an important factor in the regulation of transcriptional output. However, information on chromatin architecture on nuclear scale in fully differentiated cells, under physiological conditions and in live organisms, is largely unavailable. Here, we imaged nuclei and chromatin in muscle fibers of live, intact Drosophila larvae. In contrast to the common view that chromatin is distributed throughout the nuclear volume, we show that the entire chromatin, including active and repressed regions, forms a peripheral layer underneath the nuclear lamina, leaving a chromatin-devoid compartment at the nucleus center. Importantly, visualization of nuclear compartmentalization required imaging of un-fixed nuclei embedded within their intrinsic tissue environment, with preserved nuclear volume. Upon fixation of similar muscle nuclei, we observed an average of three-fold reduction in nuclear volume caused by dehydration and evidenced by nuclear flattening. In these conditions, the peripheral chromatin layer was not detected anymore, demonstrating the importance of preserving native biophysical tissue environment. We further show that nuclear compartmentalization is sensitive to the levels of lamin C, since over-expression of lamin C-GFP in muscle nuclei resulted in detachment of the peripheral chromatin layer from the lamina and its collapse into the nuclear center. Computer simulations of chromatin distribution recapitulated the peripheral chromatin organization observed experimentally, when binding of lamina associated domains (LADs) was incorporated with chromatin selfattractive interactions. Reducing the number of LADs led to collapse of the chromatin, similarly to our observations following lamin C over-expression. Taken together, our findings reveal a novel mode of mesoscale organization of chromatin within the nucleus in a live organism, in which the chromatin forms a peripheral layer separated from the nuclear interior.This architecture may be essential for robust transcriptional regulation in fully differentiated cells.

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“…Most of the genetic material in eukaryotic cells is packed in the nucleus with a spatial arrangement that reflects its biological function ( 1 ). This strict organization allows cells to coordinate genome-related functions in faithful ways while misregulations of nuclear organization can cause diseases ( 2 ).…”

Section: Introductionmentioning

confidence: 99%

Recent advances in the nucleolar responses to DNA double-strand breaks

Korsholm

Gál

Nieto

et al. 2020

Nucleic Acids Research

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DNA damage poses a serious threat to human health and cells therefore continuously monitor and repair DNA lesions across the genome. Ribosomal DNA is a genomic domain that represents a particular challenge due to repetitive sequences, high transcriptional activity and its localization in the nucleolus, where the accessibility of DNA repair factors is limited. Recent discoveries have significantly extended our understanding of how cells respond to DNA double-strand breaks (DSBs) in the nucleolus, and new kinases and multiple down-stream targets have been identified. Restructuring of the nucleolus can occur as a consequence of DSBs and new data point to an active regulation of this process, challenging previous views. Furthermore, new insights into coordination of cell cycle phases and ribosomal DNA repair argue against existing concepts. In addition, the importance of nucleolar-DNA damage response (n-DDR) mechanisms for maintenance of genome stability and the potential of such factors as anti-cancer targets is becoming apparent. This review will provide a detailed discussion of recent findings and their implications for our understanding of the n-DDR. The n-DDR shares features with the DNA damage response (DDR) elsewhere in the genome but is also emerging as an independent response unique to ribosomal DNA and the nucleolus.

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Radial Organization in the Mammalian Nucleus

Cited by 37 publications

References 133 publications

A Paradigm Revolution or Just Better Resolution—Will Newly Emerging Superresolution Techniques Identify Chromatin Architecture as a Key Factor in Radiation-Induced DNA Damage and Repair Regulation?

A Paradigm Revolution or Just Better Resolution—Will Newly Emerging Superresolution Techniques Identify Chromatin Architecture as a Key Factor in Radiation-Induced DNA Damage and Repair Regulation?

Live imaging of chromatin distribution in muscle nuclei reveals novel principles of nuclear architecture and chromatin compartmentalization

Recent advances in the nucleolar responses to DNA double-strand breaks

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