scholarly journals The Last Chance Saloon

2021 ◽  
Vol 9 ◽  
Author(s):  
Ye Hong ◽  
Hongtao Zhang ◽  
Anton Gartner
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Chromosome Segregation ◽  
Cell Cycle Progression ◽  
Genome Instability ◽  
Genome Integrity ◽  
Cycle Progression ◽  
Chromosome Fragmentation ◽  
C Elegans ◽  
Chromatin Bridges

Accurate chromosome segregation requires the removal of all chromatin bridges, which link chromosomes before cell division. When chromatin bridges fail to be removed, cell cycle progression may halt, or cytokinesis failure and ensuing polyploidization may occur. Conversely, the inappropriate severing of chromatin bridges leads to chromosome fragmentation, excessive genome instability at breakpoints, micronucleus formation, and chromothripsis. In this mini-review, we first describe the origins of chromatin bridges, the toxic processing of chromatin bridges by mechanical force, and the TREX1 exonuclease. We then focus on the abscission checkpoint (NoCut) which can confer a transient delay in cytokinesis progression to facilitate bridge resolution. Finally, we describe a recently identified mechanism uncovered in C. elegans where the conserved midbody associated endonuclease LEM-3/ANKLE1 is able to resolve chromatin bridges generated by various perturbations of DNA metabolism at the final stage of cell division. We also discuss how LEM-3 dependent chromatin bridge resolution may be coordinated with abscission checkpoint (NoCut) to achieve an error-free cleavage, therefore acting as a “last chance saloon” to facilitate genome integrity and organismal survival.

scholarly journals Regulation of Cell Division in Bacteria by Monitoring Genome Integrity and DNA Replication Status

2019 ◽  
Vol 202 (2) ◽  
Author(s):  
Peter E. Burby ◽  
Lyle A. Simmons
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Division ◽  
Dna Replication ◽  
Cell Cycle Progression ◽  
Genome Instability ◽  
Sos Response ◽  
Bacterial Cells ◽  
Cycle Progression ◽  
Content Type

ABSTRACT All organisms regulate cell cycle progression by coordinating cell division with DNA replication status. In eukaryotes, DNA damage or problems with replication fork progression induce the DNA damage response (DDR), causing cyclin-dependent kinases to remain active, preventing further cell cycle progression until replication and repair are complete. In bacteria, cell division is coordinated with chromosome segregation, preventing cell division ring formation over the nucleoid in a process termed nucleoid occlusion. In addition to nucleoid occlusion, bacteria induce the SOS response after replication forks encounter DNA damage or impediments that slow or block their progression. During SOS induction, Escherichia coli expresses a cytoplasmic protein, SulA, that inhibits cell division by directly binding FtsZ. After the SOS response is turned off, SulA is degraded by Lon protease, allowing for cell division to resume. Recently, it has become clear that SulA is restricted to bacteria closely related to E. coli and that most bacteria enforce the DNA damage checkpoint by expressing a small integral membrane protein. Resumption of cell division is then mediated by membrane-bound proteases that cleave the cell division inhibitor. Further, many bacterial cells have mechanisms to inhibit cell division that are regulated independently from the canonical LexA-mediated SOS response. In this review, we discuss several pathways used by bacteria to prevent cell division from occurring when genome instability is detected or before the chromosome has been fully replicated and segregated.

scholarly journals Human ANKLE1 is a nuclease specific for branched DNA

2020 ◽  
Author(s):  
Junfang Song ◽  
Alasdair D. J. Freeman ◽  
Axel Knebel ◽  
Anton Gartner ◽  
David M. J. Lilley
Keyword(s):  
Chromosome Segregation ◽  
Cell Cycle Progression ◽  
Genome Integrity ◽  
Substrate Selectivity ◽  
Cycle Progression ◽  
C Elegans ◽  
Dna Junctions ◽  
Sister Chromatids ◽  
Branched Dna ◽  
Late Stages

ABSTRACTAll physical connections between sister chromatids must be broken before cells can divide, and eukaryotic cells have evolved multiple ways in which to process branchpoints connecting DNA molecules separated both spatially and temporally. A single DNA link between chromatids has the potential to disrupt cell cycle progression and genome integrity, so it is highly likely that cells require a nuclease that can process remaining unresolved and hemi-resolved DNA junctions and other branched species at the very late stages of mitosis. We argue that ANKLE1 probably serves this function in human cells (LEM-3 in C. elegans). LEM-3 has previously been shown to be located at the cell mid-body, and we show here that human ANKLE1 is a nuclease that cleaves a range of branched DNA species. It thus has the substrate selectivity consistent with an enzyme required to process a variety of unresolved and hemi-resolved branchpoints in DNA. Our results imply that ANKLE1 acts as a catch-all enzyme of last resort that allows faithful chromosome segregation and cell division to occur.

scholarly journals DNA replication and mitotic entry: A brake model for cell cycle progression

2019 ◽  
Vol 218 (12) ◽  
pp. 3892-3902 ◽  
Author(s):  
Bennie Lemmens ◽  
Arne Lindqvist
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Dna Replication ◽  
Cell Cycle Progression ◽  
Genome Instability ◽  
Cycle Model ◽  
Cycle Progression ◽  
Daughter Cells ◽  
Core Function ◽  
A Cell

The core function of the cell cycle is to duplicate the genome and divide the duplicated DNA into two daughter cells. These processes need to be carefully coordinated, as cell division before DNA replication is complete leads to genome instability and cell death. Recent observations show that DNA replication, far from being only a consequence of cell cycle progression, plays a key role in coordinating cell cycle activities. DNA replication, through checkpoint kinase signaling, restricts the activity of cyclin-dependent kinases (CDKs) that promote cell division. The S/G2 transition is therefore emerging as a crucial regulatory step to determine the timing of mitosis. Here we discuss recent observations that redefine the coupling between DNA replication and cell division and incorporate these insights into an updated cell cycle model for human cells. We propose a cell cycle model based on a single trigger and sequential releases of three molecular brakes that determine the kinetics of CDK activation.

scholarly journals Analysis of Cell Cycle and Replication of Mouse Macrophages afterIn VivoandIn VitroCryptococcus neoformans Infection Using Laser Scanning Cytometry

2012 ◽  
Vol 80 (4) ◽  
pp. 1467-1478 ◽  
Author(s):  
Carolina Coelho ◽  
Lydia Tesfa ◽  
Jinghang Zhang ◽  
Johanna Rivera ◽  
Teresa Gonçalves ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Cytotoxic Effect ◽  
Laser Scanning ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Content Type ◽  
Cycle Arrest ◽  
Laser Scanning Cytometry

ABSTRACTWe investigated the outcome of the interaction ofCryptococcus neoformanswith murine macrophages using laser scanning cytometry (LSC). Previous results in our lab had shown that phagocytosis ofC. neoformanspromoted cell cycle progression. LSC allowed us to simultaneously measure the phagocytic index, macrophage DNA content, and 5-ethynyl-2′-deoxyuridine (EdU) incorporation such that it was possible to study host cell division as a function of phagocytosis. LSC proved to be a robust, reliable, and high-throughput method for quantifying phagocytosis. Phagocytosis ofC. neoformanspromoted cell cycle progression, but infected macrophages were significantly less likely to complete mitosis. Hence, we report a new cytotoxic effect associated with intracellularC. neoformansresidence that manifested itself in impaired cell cycle completion as a consequence of a block in the G2/M stage of the mitotic cell cycle. Cell cycle arrest was not due to increased cell membrane permeability or DNA damage. We investigated alveolar macrophage replicationin vivoand demonstrated that these cells are capable of low levels of cell division in the presence or absence ofC. neoformansinfection. In summary, we simultaneously studied phagocytosis, the cell cycle state of the host cell and pathogen-mediated cytotoxicity, and our results demonstrate a new cytotoxic effect ofC. neoformansinfection on murine macrophages: fungus-induced cell cycle arrest. Finally, we provide evidence for alveolar macrophage proliferationin vivo.

scholarly journals Developmental HCN channelopathy results in decreased neural progenitor proliferation and microcephaly in mice

2021 ◽  
Author(s):  
Anna Katharina Schlusche ◽  
Sabine Ulrike Vay ◽  
Niklas Kleinenkuhnen ◽  
Steffi Sandke ◽  
Rafael Campos-Martin ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Membrane Potential ◽  
Cell Cycle Progression ◽  
Cortical Development ◽  
General Mechanism ◽  
Hcn Channel ◽  
Cycle Progression ◽  
Channel Function ◽  
Stem And Progenitor Cells

ABSTRACTThe development of the cerebral cortex relies on the controlled division of neural stem and progenitor cells. The requirement for precise spatiotemporal control of proliferation and cell fate places a high demand on the cell division machinery, and defective cell division can cause microcephaly and other brain malformations. Cell-extrinsic and intrinsic factors govern the capacity of cortical progenitors to produce large numbers of neurons and glia within a short developmental time window. In particular, ion channels shape the intrinsic biophysical properties of precursor cells and neurons and control their membrane potential throughout the cell cycle. We found that hyperpolarization-activated cyclic nucleotide-gated cation (HCN)-channel subunits are expressed in mouse, rat, and human neural progenitors. Loss of HCN-channel function in rat neural stem cells impaired their proliferation by affecting the cell-cycle progression, causing G1 accumulation and dysregulation of genes associated with human microcephaly. Transgene-mediated, dominant-negative loss of HCN-channel function in the embryonic mouse telencephalon resulted in pronounced microcephaly. Together, our findings suggest a novel role for HCN-channel subunits as a part of a general mechanism influencing cortical development in mammals.Significance StatementImpaired cell cycle regulation of neural stem and progenitor cells can affect cortical development and cause microcephaly. During cell cycle progression, the cellular membrane potential changes through the activity of ion channels and tends to be more depolarized in proliferating cells. HCN channels, which mediate a depolarizing current in neurons and cardiac cells, are linked to neurodevelopmental diseases, also contribute to the control of cell-cycle progression and proliferation of neuronal precursor cells. In this study, HCN-channel deficiency during embryonic and fetal brain development resulted in marked microcephaly of mice designed to be deficient in HCN-channel function in dorsal forebrain progenitors. The findings suggest that HCN-channel subunits are part of a general mechanism influencing cortical development in mammals.

scholarly journals Non‐redundant functions of H2A.Z.1 and H2A.Z.2 in chromosome segregation and cell cycle progression

EMBO Reports ◽  
2021 ◽  
Author(s):  
Raquel Sales‐Gil ◽  
Dorothee C Kommer ◽  
Ines J Castro ◽  
Hasnat A Amin ◽  
Veronica Vinciotti ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Chromosome Segregation ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Redundant Functions

The regulation of the DNA damage response at telomeres: focus on kinases

2021 ◽  
Author(s):  
Michela Galli ◽  
Chiara Frigerio ◽  
Maria Pia Longhese ◽  
Michela Clerici
Keyword(s):  
Cell Cycle ◽  
Cellular Response ◽  
Cell Cycle Progression ◽  
Binding Proteins ◽  
Replicative Senescence ◽  
Genome Instability ◽  
Cycle Progression ◽  
Strand Breaks ◽  
Cycle Arrest ◽  
Linear Chromosomes

The natural ends of linear chromosomes resemble those of accidental double-strand breaks (DSBs). DSBs induce a multifaceted cellular response that promotes the repair of lesions and slows down cell cycle progression. This response is not elicited at chromosome ends, which are organized in nucleoprotein structures called telomeres. Besides counteracting DSB response through specialized telomere-binding proteins, telomeres also prevent chromosome shortening. Despite of the different fate of telomeres and DSBs, many proteins involved in the DSB response also localize at telomeres and participate in telomere homeostasis. In particular, the DSB master regulators Tel1/ATM and Mec1/ATR contribute to telomere length maintenance and arrest cell cycle progression when chromosome ends shorten, thus promoting a tumor-suppressive process known as replicative senescence. During senescence, the actions of both these apical kinases and telomere-binding proteins allow checkpoint activation while bulk DNA repair activities at telomeres are still inhibited. Checkpoint-mediated cell cycle arrest also prevents further telomere erosion and deprotection that would favor chromosome rearrangements, which are known to increase cancer-associated genome instability. This review summarizes recent insights into functions and regulation of Tel1/ATM and Mec1/ATR at telomeres both in the presence and in the absence of telomerase, focusing mainly on discoveries in budding yeast.

Sign in / Sign up

Export Citation Format

Share Document