Regulation of Nuclear Mechanics and the Impact on DNA Damage

Santos, Ália dos; Toseland, Christopher P.

doi:10.3390/ijms22063178

Cited by 31 publications

(46 citation statements)

References 161 publications

(136 reference statements)

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“…As the cytoskeleton is one of the major contributors to nuclear shape 19 and we noticed abnormal microtubule organization among SRSF2 Mut cells after exposure to RKI-1447, we next examined the general effects of the mutation and the RKI-1447 on the cells’ structure. Three-dimensional confocal imaging of WT and mutant cells, either untreated or treated with RKI-1447, were performed and revealed major differences in general nuclear morphology both before RKI-1447 and after.…”

Section: Resultsmentioning

confidence: 99%

Rock inhibitors target SRSF2 leukemia by disrupting cell mitosis and nuclear morphology

Fleisher

Grosheva

et al. 2022

Preprint

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Spliceosome machinery mutations are common early mutations in myeloid malignancies, however effective targeted therapies against them are still lacking. In the current study, we used an in vitro high-throughput drug screen among four different isogenic cell lines and identified ROCK inhibitors (ROCKi) as selective inhibitors of SRSF2 mutants. ROCKi targeted SRSF2 Mut primary human samples in a xenografts model and were not toxic to mice nor human cells. ROCKi induced mitotic catastrophe through their apparent effects on microtubules and nuclear organization. Transmission electron microscopy revealed that SRSF2 mutations induce deep nuclear indentation and segmentation, driven by microtubule-rich cytoplasmic intrusions, which were exacerbated by ROCKi. The severe nuclear deformation driven by the combination of SRSF2 Mut and ROCKi prevent cells from completing mitosis. These findings shed light on new ways to target SRSF2 and on the role of the microtubule system in SRSF2 Mut cells.

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Section: Resultsmentioning

confidence: 99%

Rock inhibitors target SRSF2 leukemia by disrupting cell mitosis and nuclear morphology

Fleisher

Grosheva

et al. 2022

Preprint

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“…Additionally, nuclear pore complexes, which fuse the two layers of the nuclear envelope, are mechanosensitive thereby making the nucleus itself sensitive to changes in cellular mechanical forces [38][39][40]. The four main contributing factors to the shape of a cell's nucleus are cytoskeletal forces, the thickness of the nuclear lamina, level of chromatin compaction, and activity of proteins that control chromatin conformation [41]. Here, we demonstrate significant nuclear elongation of astrocytes following TE-RMS formation, with some astrocytes having a nuclear aspect ratio as high as 8.…”

Section: Discussionmentioning

confidence: 99%

“…We are currently exploring the occurrence of similar structural changes in the TE-RMS fabricated from human astrocyte-like cells, and examining the consequences of these structural changes, including how gene expression regulation changes with TE-RMS formation and the resulting consequences for astrocyte physiology and function. It is well known that mechanical changes in nuclear morphology are often accompanied by changes in chromatin organization and gene expression which then lead to downstream alterations in cell activity and signaling [41,[51][52][53][54]. However, there is limited research on how mechanically altering nuclear shape affects gene expression regulation and cell behavior in astrocytes specifically [44,45].…”

Section: Discussionmentioning

confidence: 99%

Unique Astrocyte Cytoskeletal and Nuclear Morphology in a Three-Dimensional Tissue-Engineered Rostral Migratory Stream

2022

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Neural precursor cells (NPCs) are generated in the subventricular zone (SVZ) and travel through the rostral migratory stream (RMS) to replace olfactory bulb interneurons in the brains of most adult mammals. Following brain injury, SVZ-derived NPCs can divert from the RMS and migrate toward injured brain regions but arrive in numbers too low to promote functional recovery without experimental intervention. Our lab has biofabricated a “living scaffold” that replicates the structural and functional features of the endogenous RMS. This tissue-engineered rostral migratory stream (TE-RMS) is a new regenerative medicine strategy designed to facilitate stable and sustained NPC delivery into neuron-deficient brain regions following brain injury or neurodegenerative disease and an in vitro tool to investigate the mechanisms of neuronal migration and cell–cell communication. We have previously shown that the TE-RMS replicates the basic structure and protein expression of the endogenous RMS and can direct immature neuronal migration in vitro and in vivo. Here, we further describe profound morphological changes that occur following precise physical manipulation and subsequent self-assembly of astrocytes into the TE-RMS, including significant cytoskeletal rearrangement and nuclear elongation. The unique cytoskeletal and nuclear architecture of TE-RMS astrocytes mimics astrocytes in the endogenous rat RMS. Advanced imaging techniques reveal the unique morphology of TE-RMS cells that has yet to be described of astrocytes in vitro. The TE-RMS offers a novel platform to elucidate astrocyte cytoskeletal and nuclear dynamics and their relationship to cell behavior and function.

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“…Although the interactions between lamins and chromatin are critical to the organization of each, the network of chromatin within the nucleus provides a functionally separate mechanotransduction mechanism (Turgay et al, 2017;Dos Santos and Toseland, 2021).…”

Section: Lamina and Nuclear Envelopementioning

confidence: 99%

The Nucleoskeleton: Crossroad of Mechanotransduction in Skeletal Muscle

2021

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Intermediate filaments (IFs) are a primary structural component of the cytoskeleton extending throughout the muscle cell (myofiber). Mechanotransduction, the process by which mechanical force is translated into a biochemical signal to activate downstream cellular responses, is crucial to myofiber function. Mechanical forces also act on the nuclear cytoskeleton, which is integrated with the myofiber cytoskeleton by the linker of the nucleoskeleton and cytoskeleton (LINC) complexes. Thus, the nucleus serves as the endpoint for the transmission of force through the cell. The nuclear lamina, a dense meshwork of lamin IFs between the nuclear envelope and underlying chromatin, plays a crucial role in responding to mechanical input; myofibers constantly respond to mechanical perturbation via signaling pathways by activation of specific genes. The nucleus is the largest organelle in cells and a master regulator of cell homeostasis, thus an understanding of how it responds to its mechanical environment is of great interest. The importance of the cell nucleus is magnified in skeletal muscle cells due to their syncytial nature and the extreme mechanical environment that muscle contraction creates. In this review, we summarize the bidirectional link between the organization of the nucleoskeleton and the contractile features of skeletal muscle as they relate to muscle function.

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Regulation of Nuclear Mechanics and the Impact on DNA Damage

Cited by 31 publications

References 161 publications

Rock inhibitors target SRSF2 leukemia by disrupting cell mitosis and nuclear morphology

Rock inhibitors target SRSF2 leukemia by disrupting cell mitosis and nuclear morphology

Unique Astrocyte Cytoskeletal and Nuclear Morphology in a Three-Dimensional Tissue-Engineered Rostral Migratory Stream

The Nucleoskeleton: Crossroad of Mechanotransduction in Skeletal Muscle

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