Search Results (10)

Individual cells and cells within the tissues and organs constantly face mechanical challenges, such as tension, compression, strain, shear stress, and the rigidity of cellular and extracellular surroundings. Besides the external mechanical forces, cells and their components are also subjected to intracellular mechanical forces, such as pulling, pushing, and stretching, created by the sophisticated force-generation machinery of the cytoskeleton and molecular motors. All these mechanical stressors switch on the mechanotransduction pathways, allowing cells and their components to respond and adapt. Mechanical force-induced changes at the cell membrane and cytoskeleton are also transmitted to the nucleus and its nucleoskeleton, affecting nucleocytoplasmic transport, chromatin conformation, transcriptional activity, replication, and genome, which, in turn, orchestrate cellular mechanical behavior. The memory of mechanoresponses is stored as epigenetic and chromatin structure modifications. The mechanical state of the cell in response to the acellular and cellular environment also determines cell identity, fate, and immune response to invading pathogens. Here, we give a short overview of the latest developments in understanding these processes, emphasizing their effects on cell nuclei, chromosomes, and chromatin. Full article

Down syndrome (DS) is characterised by a duplication of chromosome-21 and is linked to co-occurring physical and mental health conditions, including low self-efficacy and disturbed mood states. The purpose of this study was to investigate the effects of an eight-week prescribed physical and/or cognitive training intervention on measures of mood disturbance, life satisfaction and self-efficacy in a population of adults with DS. Eighty-three participants (age 27.1 ± 8.0 years) from across five continents volunteered. Participants were assigned using matched groups based upon performance in a modified six-minute walk test to either an exercise (EXE) 3 × 30 min of walking/jogging per week, cognitive training (COG) 6 × 20 min per week, a combined group (COM) or the control (CON) who did not complete any intervention. Profile of Mood States (POMS) were assessed using a five-point scale across 65 categories pre- and post-study as well as upon completion of each week of the intervention. In addition, Satisfaction with Life Scale (SWLS) and self-efficacy using the Generalised Self-Efficacy scale (GSE) were recorded before and after the intervention. GSE increased for all participants by 1.9 ± 5.2 (p = 0.002) from pre- to post-intervention, while POMS showed significant changes for the whole group from pre- to post-intervention for tension (p < 0.001), depression (p < 0.001) and for anger (p < 0.001). In addition, significant correlations were observed between SWLS and ΔTMD, Δtension, Δanger, and Δfatigue (p < 0.05) for EXE. Both COG and EXE provide a framework for empowering enhancements in life satisfaction, self-efficacy and mood states fostering improvements in quality of life. Full article

Accurate chromosome segregation depends on bipolar chromosome–microtubule attachment and tension generation on chromosomes. Incorrect chromosome attachment results in chromosome missegregation, which contributes to genome instability. The kinetochore is a protein complex that localizes at the centromere region of a chromosome and mediates chromosome–microtubule interaction. Incorrect chromosome attachment leads to checkpoint activation to prevent anaphase onset. Kinetochore detachment activates the spindle assembly checkpoint (SAC), while tensionless kinetochore attachment relies on both the SAC and tension checkpoint. In budding yeast Saccharomyces cerevisiae, kinesin-5 motor proteins Cin8 and Kip1 are needed to separate spindle pole bodies for spindle assembly, and deletion of CIN8 causes lethality in the absence of SAC. To study the function of Cin8 and Kip1 in chromosome segregation, we constructed an auxin-inducible degron (AID) mutant, cin8-AID. With this conditional mutant, we first confirmed that cin8-AID kip1∆ double mutants were lethal when Cin8 is depleted in the presence of auxin. These cells arrested in metaphase with unseparated spindle pole bodies and kinetochores. We further showed that the absence of either the SAC or tension checkpoint was sufficient to abolish the cell-cycle delay in cin8-AID mutants, causing chromosome missegregation and viability loss. The tension checkpoint-dependent phenotype in cells with depleted Cin8 suggests the presence of tensionless chromosome attachment. We speculate that the failed spindle pole body separation in cin8 mutants could increase the chance of tensionless syntelic chromosome attachments, which depends on functional tension checkpoint for survival. Full article

For correct chromosome segregation in mitosis, eukaryotic cells must establish chromosome biorientation where sister kinetochores attach to microtubules extending from opposite spindle poles. To establish biorientation, any aberrant kinetochore–microtubule interactions must be resolved in the process called error correction. For resolution of the aberrant interactions in error correction, kinetochore–microtubule interactions must be exchanged until biorientation is formed (the SWAP process). At initiation of biorientation, the state of weak kinetochore–microtubule interactions should be converted to the state of stable interactions (the SWITCH process)—the conundrum of this conversion is called the initiation problem of biorientation. Once biorientation is established, tension is applied on kinetochore–microtubule interactions, which stabilizes the interactions (the STABILIZE process). Aurora B kinase plays central roles in promoting error correction, and Mps1 kinase and Stu2 microtubule polymerase also play important roles. In this article, we review mechanisms of error correction by considering the SWAP, SWITCH, and STABILIZE processes. We mainly focus on mechanisms found in budding yeast, where only one microtubule attaches to a single kinetochore at biorientation, making the error correction mechanisms relatively simpler. Full article

The abscission checkpoint contributes to the fidelity of chromosome segregation by delaying completion of cytokinesis (abscission) when there is chromatin lagging in the intercellular bridge between dividing cells. Although additional triggers of an abscission checkpoint-delay have been described, including nuclear pore defects, replication stress or high intercellular bridge tension, this review will focus only on chromatin bridges. In the presence of such abnormal chromosomal tethers in mammalian cells, the abscission checkpoint requires proper localization and optimal kinase activity of the Chromosomal Passenger Complex (CPC)-catalytic subunit Aurora B at the midbody and culminates in the inhibition of Endosomal Sorting Complex Required for Transport-III (ESCRT-III) components at the abscission site to delay the final cut. Furthermore, cells with an active checkpoint stabilize the narrow cytoplasmic canal that connects the two daughter cells until the chromatin bridges are resolved. Unsuccessful resolution of chromatin bridges in checkpoint-deficient cells or in cells with unstable intercellular canals can lead to chromatin bridge breakage or tetraploidization by regression of the cleavage furrow. In turn, these outcomes can lead to accumulation of DNA damage, chromothripsis, generation of hypermutation clusters and chromosomal instability, which are associated with cancer formation or progression. Recently, many important questions regarding the mechanisms of the abscission checkpoint have been investigated, such as how the presence of chromatin bridges is signaled to the CPC, how Aurora B localization and kinase activity is regulated in late midbodies, the signaling pathways by which Aurora B implements the abscission delay, and how the actin cytoskeleton is remodeled to stabilize intercellular canals with DNA bridges. Here, we review recent progress toward understanding the mechanisms of the abscission checkpoint and its role in guarding genome integrity at the chromosome level, and consider its potential implications for cancer therapy. Full article

The accurate segregation of chromosomes is essential for the survival of organisms and cells. Mistakes can lead to aneuploidy, tumorigenesis and congenital birth defects. The spindle assembly checkpoint ensures that chromosomes properly align on the spindle, with sister chromatids attached to microtubules from opposite poles. Here, we review how tension is used to identify and selectively destabilize incorrect attachments, and thus serves as a trigger of the spindle assembly checkpoint to ensure fidelity in chromosome segregation. Tension is generated on properly attached chromosomes as sister chromatids are pulled in opposing directions but resisted by centromeric cohesin. We discuss the role of the Aurora B kinase in tension-sensing and explore the current models for translating mechanical force into Aurora B-mediated biochemical signals that regulate correction of chromosome attachments to the spindle. Full article

Cell proliferation and sexual reproduction require the faithful segregation of chromosomes. Chromosome segregation is driven by the interaction of chromosomes with the spindle, and the attachment of chromosomes to the proper spindle poles is essential. Initial attachments are frequently erroneous due to the random nature of the attachment process; however, erroneous attachments are selectively eliminated. Proper attachment generates greater tension at the kinetochore than erroneous attachments, and it is thought that attachment selection is dependent on this tension. However, studies of meiotic chromosome segregation suggest that attachment elimination cannot be solely attributed to tension, and the precise mechanism of selective elimination of erroneous attachments remains unclear. During attachment elimination, chromosomes oscillate between the spindle poles. A recent study on meiotic chromosome segregation in fission yeast has suggested that attachment elimination is coupled to chromosome oscillation. In this review, the possible contribution of chromosome oscillation in the elimination of erroneous attachment is discussed in light of the recent finding. Full article

Both the pericentromere and the nucleolus have unique characteristics that distinguish them amongst the rest of genome. Looping of pericentromeric DNA, due to structural maintenance of chromosome (SMC) proteins condensin and cohesin, drives its ability to maintain tension during metaphase. Similar loops are formed via condensin and cohesin in nucleolar ribosomal DNA (rDNA). Condensin and cohesin are also concentrated in transfer RNA (tRNA) genes, genes which may be located within the pericentromere as well as tethered to the nucleolus. Replication fork stalling, as well as downstream consequences such as genomic recombination, are characteristic of both the pericentromere and rDNA. Furthermore, emerging evidence suggests that the pericentromere may function as a liquid–liquid phase separated domain, similar to the nucleolus. We therefore propose that the pericentromere and nucleolus, in part due to their enrichment of SMC proteins and others, contain similar domains that drive important cellular activities such as segregation, stability, and repair. Full article

We review recent studies dealing with the molecular genetics and basic results of omics analysis of uterine leiomyoma (LM)—a common benign muscle tumor of the uterus. Whole genome studies of LM resulted in the discovery of many new gene nets and biological pathways, including its origin, transcriptomic, and epigenetic profiles, as well as the impact of the inter-cell matrix in LM growth and involvement of microRNA in its regulation. New data on somatic cell mutations ultimately involved in the origin, distribution and growth of LM are reviewed. Putative identification of LM progenitor SC (stem cells) giving rise to maternal fibroid nodes and junctional zones provide a new clue for hypotheses on the pathogenomics of LM. The reviewed data are consistent with at least two different but probably intimately interacted molecular mechanisms of LM. One of them (the genetic hypothesis) is focused primarily on the MED12 gene mutations and suggests its onset in the side population of embryonic myoblasts of the female reproductive system, which later gave rise to multiple small and medium fibroids. The single and usually large-size fibroids are induced by predominantly epigenetic disorders in LM SC, provoked by enhanced expression of the HMGA2 gene caused by its hypomethylation and epigenetic deregulation enhanced by hypoxia, muscle tension, or chromosome instability/aberrations. The pathogenomics of both genetic and epigenetic programs of LM with many peculiarities at the beginning later became rather similar and partly overlapped due to the proximity of their gene nets and epigenetic landscape. Pathogenomic studies of LM open ways for elaboration of novel strategies of prevention and treatment of this common disease. Full article

The mitotic spindle segregates chromosomes into two daughter cells during cell division. This process relies on the precise regulation of forces acting on chromosomes as the cell progresses through mitosis. The forces in the spindle are difficult to directly measure using the available experimental techniques. Here, we review the ideas and recent advances of how forces can be determined from the spindle shape. By using these approaches, it has been shown that tension and compression coexist along a single kinetochore fiber, which are balanced by a bridging fiber between sister kinetochore fibers. An extension of this approach to three dimensions revealed that microtubule bundles have rich shapes, and extend not simply like meridians on the Earth’s surface but, rather, twisted in a helical manner. Such complex shapes are due to rotational forces, which, in addition to linear forces, act in the spindle and may be generated by motor proteins such as kinesin-5. These findings open new questions for future studies, to understand the mechanisms of rotational forces and reveal their biological roles in cells. Full article