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Current Genetics Feb 2016Cycling events in nature start and end to restart again and again. In the cell cycle, whose purpose is to become two where there was only one, cyclin-dependent kinases... (Review)
Review
Cycling events in nature start and end to restart again and again. In the cell cycle, whose purpose is to become two where there was only one, cyclin-dependent kinases (CDKs) are the beginning and, therefore, phosphatases must play a role in the ending. Since CDKs are drivers of the cell cycle and cancer cells uncontrollably divide, much attention has been put into knocking down CDK activity. However, much less is known on the consequences of interfering with the phosphatases that put an end to the cell cycle. We have addressed in recent years the consequences of transiently inactivating the only master cell cycle phosphatase in the model yeast Saccharomyces cerevisiae, Cdc14. Transient inactivation is expected to better mimic the pharmacological action of drugs. Interestingly, we have found that yeast cells tolerate badly a relatively brief inactivation of Cdc14 when cells are already committed into anaphase, the first cell cycle stage where this phosphatase plays important roles. First, we noticed that the segregation of distal regions in the chromosome arm that carries the ribosomal DNA array was irreversibly impaired, leading to an anaphase bridge (AB). Next, we found that this AB could eventually be severed by cytokinesis and led to two different types of genetically compromised daughter cells. All these previous studies were done in haploid cells. We have now recently expanded this analysis to diploid cells and used the advantage of making hybrid diploids to study chromosome rearrangements and changes in the ploidy of the surviving progeny. We have found that the consequences for the genome integrity were far more dramatic than originally envisioned.
Topics: Anaphase; Cell Cycle; Cell Cycle Proteins; Chromosome Segregation; Chromosomes, Fungal; Mitosis; Protein Tyrosine Phosphatases; Saccharomyces cerevisiae Proteins; Sister Chromatid Exchange
PubMed: 26116076
DOI: 10.1007/s00294-015-0502-1 -
Molecular Biology of the Cell Sep 2023During anaphase, antiparallel-overlapping midzone microtubules elongate and form bundles, contributing to chromosome segregation and the location of contractile ring... (Comparative Study)
Comparative Study
During anaphase, antiparallel-overlapping midzone microtubules elongate and form bundles, contributing to chromosome segregation and the location of contractile ring formation. Midzone microtubules are dynamic in early but not late anaphase; however, the kinetics and mechanisms of stabilization are incompletely understood. Using photoactivation of cells expressing PA-EGFP-α-tubulin we find that immediately after anaphase onset, a single highly dynamic population of midzone microtubules is present; as anaphase progresses, both dynamic and stable populations of midzone microtubules coexist. By mid-cytokinesis, only static, non-dynamic microtubules are detected. The velocity of microtubule sliding also decreases as anaphase progresses, becoming undetectable by late anaphase. Following depletion of PRC1, midzone microtubules remain highly dynamic in anaphase and fail to form static arrays in telophase despite furrowing. Cells depleted of Kif4a contain elongated PRC1 overlap zones and fail to form static arrays in telophase. Cells blocked in cytokinesis form short PRC1 overlap zones that do not coalesce laterally; these cells also fail to form static arrays in telophase. Together, our results demonstrate that dynamic turnover and sliding of midzone microtubules is gradually reduced during anaphase and that the final transition to a static array in telophase requires both lateral and longitudinal compaction of PRC1 containing overlap zones.
Topics: Humans; Anaphase; Cell Cycle Proteins; Cytokinesis; Microtubules; Spindle Apparatus; Tubulin
PubMed: 37467037
DOI: 10.1091/mbc.E23-02-0049 -
Communications Biology Dec 2021Mitotic divisions achieve equal re-partition of chromosomes into daughter cells. In their recent work in , Sen, Harrison et al. propose that the risk of mis-segregation...
Mitotic divisions achieve equal re-partition of chromosomes into daughter cells. In their recent work in , Sen, Harrison et al. propose that the risk of mis-segregation in human mitotic cells is higher than previously thought and identify the existence of an early-anaphase correction mechanism. The study documents kinetochore dynamics in unprecedented detail, providing a detailed look at the events preceding loss of correct chromosomal numericity and genomic stability.
Topics: Anaphase; Chromosome Segregation; Humans; Kinetochores; Mitosis
PubMed: 34903809
DOI: 10.1038/s42003-021-02933-1 -
Cell Cycle (Georgetown, Tex.) 2015Faithful chromosome segregation is critical in preventing genome loss or damage during cell division. Failure to properly disentangle catenated sister chromatids can... (Review)
Review
Faithful chromosome segregation is critical in preventing genome loss or damage during cell division. Failure to properly disentangle catenated sister chromatids can lead to the formation of bulky or ultrafine anaphase bridges, and ultimately genome instability. In this review we present an overview of the current state of knowledge of how sister chromatid decatenation is carried out, with particular focus on the role of TOP2A and TOPBP1 in this process.
Topics: Anaphase; Animals; Antigens, Neoplasm; Carrier Proteins; Cell Cycle; Chromatids; Chromosome Segregation; DNA Topoisomerases, Type II; DNA-Binding Proteins; Humans; Mitosis; Nuclear Proteins; Poly-ADP-Ribose Binding Proteins
PubMed: 26266709
DOI: 10.1080/15384101.2015.1078039 -
Nature Reviews. Cancer Jul 2017Ever since initial suggestions that instability at common fragile sites (CFSs) could be responsible for chromosome rearrangements in cancers, CFSs and associated genes... (Review)
Review
Ever since initial suggestions that instability at common fragile sites (CFSs) could be responsible for chromosome rearrangements in cancers, CFSs and associated genes have been the subject of numerous studies, leading to questions and controversies about their role and importance in cancer. It is now clear that CFSs are not frequently involved in translocations or other cancer-associated recurrent gross chromosome rearrangements. However, recent studies have provided new insights into the mechanisms of CFS instability, their effect on genome instability, and their role in generating focal copy number alterations that affect the genomic landscape of many cancers.
Topics: Anaphase; Animals; Chromosomal Instability; Chromosome Breakage; Chromosome Fragile Sites; DNA Breaks, Double-Stranded; DNA Copy Number Variations; DNA Replication; Gene Rearrangement; Humans; Metaphase; Neoplasms; Oncogenes
PubMed: 28740117
DOI: 10.1038/nrc.2017.52 -
Current Biology : CB Jul 2002The release of Cdc14 from the nucleolus occurs in two waves in early and late anaphase, controlled by the FEAR and MEN pathways, respectively. Two new papers report the... (Review)
Review
The release of Cdc14 from the nucleolus occurs in two waves in early and late anaphase, controlled by the FEAR and MEN pathways, respectively. Two new papers report the localisation at the spindle pole body of the Cdc14 released in early anaphase and, surprisingly, show that the two pulses of released Cdc14 have opposite effects on MEN activation.
Topics: Anaphase; Cell Cycle Proteins; Fungal Proteins; Mitosis; Phosphorylation; Protein Tyrosine Phosphatases; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 12176346
DOI: 10.1016/s0960-9822(02)00963-6 -
Cell Cycle (Georgetown, Tex.) 2014
Topics: Anaphase; Animals; Aurora Kinase B; Chromosome Segregation; Feedback, Physiological; Humans; Nuclear Envelope
PubMed: 25486554
DOI: 10.4161/15384101.2014.959853 -
ELife Oct 2022Chromosome segregation requires both the separation of sister chromatids and the sustained condensation of chromatids during anaphase. In yeast cells, cohesin is not...
Chromosome segregation requires both the separation of sister chromatids and the sustained condensation of chromatids during anaphase. In yeast cells, cohesin is not only required for sister chromatid cohesion but also plays a major role determining the structure of individual chromatids in metaphase. Separase cleavage is thought to remove all cohesin complexes from chromosomes to initiate anaphase. It is thus not clear how the length and organisation of segregating chromatids is maintained during anaphase in the absence of cohesin. Here, we show that degradation of cohesin at the anaphase onset causes aberrant chromatid segregation. Hi-C analysis on segregating chromatids demonstrates that cohesin depletion causes loss of intrachromatid organisation. Surprisingly, tobacco etch virus (TEV)-mediated cleavage of cohesin does not dramatically disrupt chromatid organisation in anaphase, explaining why bulk segregation is achieved. In addition, we identified a small pool of cohesin complexes bound to telophase chromosomes in wild-type cells and show that they play a role in the organisation of centromeric regions. Our data demonstrates that in yeast cells cohesin function is not over in metaphase, but extends to the anaphase period when chromatids are segregating.
Topics: Anaphase; Chromatids; Chromatin; Saccharomyces cerevisiae; Separase; Chromosomal Proteins, Non-Histone; Cell Cycle Proteins; Saccharomyces cerevisiae Proteins; Cohesins
PubMed: 36196991
DOI: 10.7554/eLife.80147 -
Molecular Cancer Therapeutics Mar 2021Cyclin-dependent kinase 2 (CDK2) antagonism inhibits clustering of excessive centrosomes at mitosis, causing multipolar cell division and apoptotic death. This is called...
Cyclin-dependent kinase 2 (CDK2) antagonism inhibits clustering of excessive centrosomes at mitosis, causing multipolar cell division and apoptotic death. This is called anaphase catastrophe. To establish induced anaphase catastrophe as a clinically tractable antineoplastic mechanism, induced anaphase catastrophe was explored in different aneuploid cancers after treatment with CYC065 (Cyclacel), a CDK2/9 inhibitor. Antineoplastic activity was studied in preclinical models. CYC065 treatment augmented anaphase catastrophe in diverse cancers including lymphoma, lung, colon, and pancreatic cancers, despite oncoprotein expression. Anaphase catastrophe was a broadly active antineoplastic mechanism. Reverse phase protein arrays (RPPAs) revealed that along with known CDK2/9 targets, focal adhesion kinase and Src phosphorylation that regulate metastasis were each repressed by CYC065 treatment. Intriguingly, CYC065 treatment decreased lung cancer metastases in murine models. CYC065 treatment also significantly reduced the rate of lung cancer growth in syngeneic murine and patient-derived xenograft (PDX) models independent of oncoprotein expression. Immunohistochemistry analysis of CYC065-treated lung cancer PDX models confirmed repression of proteins highlighted by RPPAs, implicating them as indicators of CYC065 antitumor response. Phospho-histone H3 staining detected anaphase catastrophe in CYC065-treated PDXs. Thus, induced anaphase catastrophe after CYC065 treatment can combat aneuploid cancers despite oncoprotein expression. These findings should guide future trials of this novel CDK2/9 inhibitor in the cancer clinic.
Topics: Anaphase; Aneuploidy; Animals; Carcinogenesis; Cell Proliferation; Cyclin-Dependent Kinase 2; Humans; Mice; Mice, Nude; Neoplasm Metastasis; Transfection
PubMed: 33277443
DOI: 10.1158/1535-7163.MCT-19-0987 -
Molecular Cell Feb 2002FtsK, which links chromosome segregation and cell division in E. coli, has now been shown to be an ATP-dependent DNA translocase. It also activates XerCD-dependent... (Review)
Review
FtsK, which links chromosome segregation and cell division in E. coli, has now been shown to be an ATP-dependent DNA translocase. It also activates XerCD-dependent recombination, converting chromosome dimers into monomers, by switching the order of strand cleavage by the recombinase subunits.
Topics: Adenosine Triphosphate; Anaphase; Bacillus; Bacterial Proteins; Chromosomes, Bacterial; DNA Nucleotidyltransferases; DNA, Bacterial; Escherichia coli; Escherichia coli Proteins; Integrases; Membrane Proteins; Protein Conformation; Recombinases; Recombination, Genetic; Sigma Factor; Transcription Factors
PubMed: 11864592
DOI: 10.1016/s1097-2765(02)00457-4