scholarly journals Asymmetric chromosome segregation and cell division in DNA damage-induced bacterial filaments

2020 ◽  
Author(s):  
Suchitha Raghunathan ◽  
Afroze Chimthanawala ◽  
Sandeep Krishna ◽  
Anthony G. Vecchiarelli ◽  
Anjana Badrinarayanan
Keyword(s):  
Dna Damage ◽  
Cell Division ◽  
Cell Size ◽  
Cell Cycle Progression ◽  
Growth Dynamics ◽  
Asymmetric Division ◽  
Wild Type ◽  
Central Function ◽  
Repair Mechanisms ◽  
Type Size

AbstractFaithful propagation of life requires coordination of DNA replication and segregation with cell growth and division. In bacteria, this results in cell size homeostasis and periodicity in replication and division. The situation is perturbed under stress such as DNA damage, which induces filamentation as cell cycle progression is blocked to allow for repair. Mechanisms that release this morphological state for re-entry into wild type growth are unclear. Here we show that damage recovery is mediated via asymmetric division of Escherichia coli filaments, producing short daughter cells with wild type size and growth dynamics. Division restoration at this polar site is governed by coordinated action of divisome positioning by the Min system and modulation of division licensing by the terminus region of the chromosome, with MatP playing a central role in this process. Collectively, our study highlights a key role for concurrency between chromosome (and specifically terminus) segregation and cell division in daughter cell size maintenance during filamentous divisions and suggests a central function for asymmetric division in mediating cellular recovery from a stressed state.

scholarly journals Asymmetric chromosome segregation and cell division in DNA damage-induced bacterial filaments

2020 ◽  
Vol 31 (26) ◽  
pp. 2920-2931
Author(s):  
Suchitha Raghunathan ◽  
Afroze Chimthanawala ◽  
Sandeep Krishna ◽  
Anthony G. Vecchiarelli ◽  
Anjana Badrinarayanan
Keyword(s):  
Dna Damage ◽  
Cell Division ◽  
Dna Damage Response ◽  
Chromosome Segregation ◽  
Asymmetric Division ◽  
Model Systems ◽  
Wild Type ◽  
Central Function ◽  
Damage Response ◽  
Bacterial Model

The DNA damage response and cell division checkpoints have been well studied in several bacterial model systems, but how cells exit such a checkpoint to restart wild-type growth is unclear. This study highlights a central function for asymmetric division in mediating cellular recovery from DNA damage.

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 Inhibition of Cell Division by the Human Cytomegalovirus IE86 Protein: Role of the p53 Pathway or Cyclin-Dependent Kinase 1/Cyclin B1

2005 ◽  
Vol 79 (4) ◽  
pp. 2597-2603 ◽  
Author(s):  
Yoon-Jae Song ◽  
Mark F. Stinski
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Human Cytomegalovirus ◽  
Cell Cycle Progression ◽  
Fibroblast Cell ◽  
Cyclin B1 ◽  
S Phase ◽  
Cyclin Dependent Kinase ◽  
Wild Type ◽  
Atm Kinase

ABSTRACT The human cytomegalovirus (HCMV) IE86 protein induces the human fibroblast cell cycle from G0/G1 to G1/S, where cell cycle progression stops. Cells with a wild-type, mutated, or null p53 or cells with null p21 protein were transduced with replication-deficient adenoviruses expressing HCMV IE86 protein or cellular p53 or p21. Even though S-phase genes were activated in a p53 wild-type cell, IE86 protein also induced phospho-Ser15 p53 and p21 independent of p14ARF but dependent on ATM kinase. These cells did not enter the S phase. In human p53 mutant, p53 null, or p21 null cells, IE86 protein did not up-regulate p21, cellular DNA synthesis was not inhibited, but cell division was inhibited. Cells accumulated in the G2/M phase, and there was increased cyclin-dependent kinase 1/cyclin B1 activity. Although the HCMV IE86 protein increases cellular E2F activity, it also blocks cell division in both p53+/+ and p53−/− cells.

scholarly journals Cardiac myosin binding protein C regulates postnatal myocyte cytokinesis

2015 ◽  
Vol 112 (29) ◽  
pp. 9046-9051 ◽  
Author(s):  
Jianming Jiang ◽  
Patrick G. Burgon ◽  
Hiroko Wakimoto ◽  
Kenji Onoue ◽  
Joshua M. Gorham ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Protein C ◽  
Cell Cycle Progression ◽  
Cardiac Myosin ◽  
Wild Type ◽  
Cycle Progression ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding

Homozygous cardiac myosin binding protein C-deficient (Mybpct/t) mice develop dramatic cardiac dilation shortly after birth; heart size increases almost twofold. We have investigated the mechanism of cardiac enlargement in these hearts. Throughout embryogenesis myocytes undergo cell division while maintaining the capacity to pump blood by rapidly disassembling and reforming myofibrillar components of the sarcomere throughout cell cycle progression. Shortly after birth, myocyte cell division ceases. Cardiac MYBPC is a thick filament protein that regulates sarcomere organization and rigidity. We demonstrate that many Mybpct/t myocytes undergo an additional round of cell division within 10 d postbirth compared with their wild-type counterparts, leading to increased numbers of mononuclear myocytes. Short-hairpin RNA knockdown of Mybpc3 mRNA in wild-type mice similarly extended the postnatal window of myocyte proliferation. However, adult Mybpct/t myocytes are unable to fully regenerate the myocardium after injury. MYBPC has unexpected inhibitory functions during postnatal myocyte cytokinesis and cell cycle progression. We suggest that human patients with homozygous MYBPC3-null mutations develop dilated cardiomyopathy, coupled with myocyte hyperplasia (increased cell number), as observed in Mybpct/t mice. Human patients, with heterozygous truncating MYBPC3 mutations, like mice with similar mutations, have hypertrophic cardiomyopathy. However, the mechanism leading to hypertrophic cardiomyopathy in heterozygous MYBPC3+/− individuals is myocyte hypertrophy (increased cell size), whereas the mechanism leading to cardiac dilation in homozygous Mybpc3−/− mice is primarily myocyte hyperplasia.

Ezh2 Is An Essential Regulator Of T-Cell Development and Oncogenic Transformation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3729-3729
Author(s):  
Camille Simon ◽  
Jalila Chagraoui ◽  
Jana Krosl ◽  
Josee Hebert ◽  
Guy Sauvageau
Keyword(s):  
Dna Damage ◽  
T Cells ◽  
Cell Division ◽  
Dna Replication ◽  
T Cell ◽  
Dna Damage Repair ◽  
Conditional Knockout ◽  
Functional Study ◽  
Wild Type ◽  
Damage Repair

Abstract Enhancer of zeste homolog 2 (EZH2) catalyzes di- and trimethylation of lysine 27 on histone H3 (H3K27me2/3) and establishes chromatin marks associated with gene silencing. We and others have recently shown that Ezh2 and its partners act as tumour suppressor genes in mouse and likely human lymphoblastic leukemia. Moreover some studies also suggest that Ezh2 is strongly required during B and T cell differentiation. However, the function of EZH2 during these processes remains unclear. For functional study we exploited an Ezh2 conditional knockout mouse model. The Cre-mediated deletion generates a mutated Ezh2Δ allele and abrogates production of EZH2 protein. Upon gene inactivation we monitored T-cell maturation and cancer development. We found that Ezh2 inactivation induces a block at the DN3-DN4 transition of TCRab+T-cells while TCRγδ T-cells were increased by 5 fold compared to wild type animals. Cell cycle analysis revealed increase in the proportions of TCRγδ+T-cells in the G2 phase compared to TCRβ+T-cells and wild type controls. This observation suggested a possibility of G2/M checkpoint activation resulting from either improper DNA replication, or a non-repaired DNA damage. Moreover we found that the Ezh2 deficient TCRγδ+ leukemia were prone to genomic instability. A majority of leukemias analyzed were aneuploid, and ∼50% were near-tetraploid. These observations were confirmed by Spectral Karyotyping (SKY), which also enabled detection of several chromosomal rearrangements. Consistent with these observations, analysis of global gene expression data from various RNA-Seq-derived datasets revealed that the genes having the highest correlation factor with Ezh2 are involved in cell division, DNA replication and DNA damage repair. Together, these studies show that Ezh2 is an essential regulator of the TCRγδ T-cell state, and prevents T-cell transformation, likely through regulation of DNA replication, cell division or DNA damage repair. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Chk2 Activation Dependence on Nbs1 after DNA Damage

2001 ◽  
Vol 21 (15) ◽  
pp. 5214-5222 ◽  
Author(s):  
Giacomo Buscemi ◽  
Camilla Savio ◽  
Laura Zannini ◽  
Francesca Miccichè ◽  
Debora Masnada ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Cycle Progression ◽  
Phosphorylation Site ◽  
Nijmegen Breakage Syndrome ◽  
Mutant Form ◽  
Dependent Manner ◽  
Wild Type ◽  
Normal Cells ◽  
Chromosome Fragility ◽  
Carboxy Terminal

ABSTRACT The checkpoint kinase Chk2 has a key role in delaying cell cycle progression in response to DNA damage. Upon activation by low-dose ionizing radiation (IR), which occurs in an ataxia telangiectasia mutated (ATM)-dependent manner, Chk2 can phosphorylate the mitosis-inducing phosphatase Cdc25C on an inhibitory site, blocking entry into mitosis, and p53 on a regulatory site, causing G1 arrest. Here we show that the ATM-dependent activation of Chk2 by γ- radiation requires Nbs1, the gene product involved in the Nijmegen breakage syndrome (NBS), a disorder that shares with AT a variety of phenotypic defects including chromosome fragility, radiosensitivity, and radioresistant DNA synthesis. Thus, whereas in normal cells Chk2 undergoes a time-dependent increased phosphorylation and induction of catalytic activity against Cdc25C, in NBS cells null for Nbs1 protein, Chk2 phosphorylation and activation are both defective. Importantly, these defects in NBS cells can be complemented by reintroduction of wild-type Nbs1, but neither by a carboxy-terminal deletion mutant of Nbs1 at amino acid 590, unable to form a complex with and to transport Mre11 and Rad50 in the nucleus, nor by an Nbs1 mutated at Ser343 (S343A), the ATM phosphorylation site. Chk2 nuclear expression is unaffected in NBS cells, hence excluding a mislocalization as the cause of failed Chk2 activation in Nbs1-null cells. Interestingly, the impaired Chk2 function in NBS cells correlates with the inability, unlike normal cells, to stop entry into mitosis immediately after irradiation, a checkpoint abnormality that can be corrected by introduction of the wild-type but not the S343A mutant form of Nbs1. Altogether, these findings underscore the crucial role of a functional Nbs1 complex in Chk2 activation and suggest that checkpoint defects in NBS cells may result from the inability to activate Chk2.

scholarly journals Regulatory networks integrating cell cycle control with DNA damage checkpoints and double-strand break repair

2011 ◽  
Vol 366 (1584) ◽  
pp. 3562-3571 ◽  
Author(s):  
Petra Langerak ◽  
Paul Russell
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Division ◽  
Regulatory Networks ◽  
Cell Cycle Progression ◽  
Cell Cycle Control ◽  
Strand Break ◽  
Dsb Repair ◽  
Cycle Progression ◽  
Non Homologous End Joining

Double-strand breaks (DSBs), arising from exposure to exogenous clastogens or as a by-product of endogenous cellular metabolism, pose grave threats to genome integrity. DSBs can sever whole chromosomes, leading to chromosomal instability, a hallmark of cancer. Healing broken DNA takes time, and it is therefore essential to temporarily halt cell division while DSB repair is underway. The seminal discovery of cyclin-dependent kinases as master regulators of the cell cycle unleashed a series of studies aimed at defining how the DNA damage response network delays cell division. These efforts culminated with the identification of Cdc25, the protein phosphatase that activates Cdc2/Cdk1, as a critical target of the checkpoint kinase Chk1. However, regulation works both ways, as recent studies have revealed that Cdc2 activity and cell cycle position determine whether DSBs are repaired by non-homologous end-joining or homologous recombination (HR). Central to this regulation are the proteins that initiate the processing of DNA ends for HR repair, Mre11–Rad50–Nbs1 protein complex and Ctp1/Sae2/CtIP, and the checkpoint kinases Tel1/ATM and Rad3/ATR. Here, we review recent findings and provide insight on how proteins that regulate cell cycle progression affect DSB repair, and, conversely how proteins that repair DSBs affect cell cycle progression.

scholarly journals Zfp423/ZNF423regulates cell cycle progression, the mode of cell division and the DNA-damage response in Purkinje neuron progenitors

Development ◽  
2017 ◽  
Vol 144 (20) ◽  
pp. 3686-3697 ◽  
Author(s):  
Filippo Casoni ◽  
Laura Croci ◽  
Camilla Bosone ◽  
Roberta D'Ambrosio ◽  
Aurora Badaloni ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Division ◽  
Dna Damage Response ◽  
Cell Cycle Progression ◽  
Purkinje Neuron ◽  
Cycle Progression ◽  
Damage Response

scholarly journals Cell Structure Changes in the Hyperthermophilic Crenarchaeon Sulfolobus islandicus Lacking the S-Layer

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Changyi Zhang ◽  
Rebecca L. Wipfler ◽  
Yuan Li ◽  
Zhiyu Wang ◽  
Emily N. Hallett ◽  
...  
Keyword(s):  
Cell Division ◽  
Cell Size ◽  
Cell Fusion ◽  
Cell Biology ◽  
Cell Structure ◽  
Evolutionary Relationship ◽  
Wild Type ◽  
Sulfolobus Islandicus ◽  
Mutant Cells

ABSTRACT Rediscovery of the ancient evolutionary relationship between archaea and eukaryotes has revitalized interest in archaeal cell biology. Key to the understanding of archaeal cells is the surface layer (S-layer), which is commonly found in Archaea but whose in vivo function is unknown. Here, we investigate the architecture and cellular roles of the S-layer in the hyperthermophilic crenarchaeon Sulfolobus islandicus. Electron micrographs of mutant cells lacking slaA or both slaA and slaB confirm the absence of the outermost layer (SlaA), whereas cells with intact or partially or completely detached SlaA are observed for the ΔslaB mutant. We experimentally identify a novel S-layer-associated protein, M164_1049, which does not functionally replace its homolog SlaB but likely assists SlaB to stabilize SlaA. Mutants deficient in the SlaA outer layer form large cell aggregates, and individual cell size varies, increasing significantly up to six times the diameter of wild-type cells. We show that the ΔslaA mutant cells exhibit more sensitivity to hyperosmotic stress but are not reduced to wild-type cell size. The ΔslaA mutant contains aberrant chromosome copy numbers not seen in wild-type cells, in which the cell cycle is tightly regulated. Together, these data suggest that the lack of SlaA results in either cell fusion or irregularities in cell division. Our studies show the key physiological and cellular functions of the S-layer in this archaeal cell. IMPORTANCE The S-layer is considered to be the sole component of the cell wall in Sulfolobales, a taxonomic group within the Crenarchaeota whose cellular features have been suggested to have a close relationship to the last archaea-eukaryote common ancestor. In this study, we genetically dissect how the two previously characterized S-layer genes as well as a newly identified S-layer-associated protein-encoding gene contribute to the S-layer architecture in Sulfolobus. We provide genetic evidence for the first time showing that the slaA gene is a key cell morphology determinant and may play a role in Sulfolobus cell division or/and cell fusion.

Variable cell division time and asymmetric division site lead to filament-to-rod cell cycle of Lysinibacillus varians

2020 ◽  
Vol 367 (7) ◽  
Author(s):  
Chunjie Zhu ◽  
Guoping Sun ◽  
Xiaoming Wang ◽  
Jun Guo ◽  
Enze Li ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Cell Size ◽  
Asymmetric Division ◽  
Division Site ◽  
Open Questions ◽  
Established Cell ◽  
Size Heterogeneity ◽  
Microscopy Techniques ◽  
Rod Cell

ABSTRACT All well-established cell size homeostasis paradigms are based on the researches of rod bacteria like B. subtilis and E. coli, suggesting a constant division time (timer model), division size (sizer model) or added size (adder model) before division. However, Lysinibacillus varians, a new species with regular filament-to-rod cell cycle, is inconsistent with existing models. In this study, the cell size parameters of the type strain GY32, were investigated by combing multiple microscopy techniques and single-cell approach. Our results showed that the filaments of strain GY32 were unicellular cells with multiple nucleoids. The division time of GY32 cells was variable and their daughter cells produced by asymmetric binary fission had different birth sizes, which were proportional to their elongation rates, resulting in high heterogeneity among the sister cells. Furthermore, the added size from birth to division was significantly shorter than birth size (p < 0.01) and decreased along generations. The results above revealed that the asymmetric division site and varied cell size parameters resulted in filament-to-rod cell cycle of L. varians and cell size homeostasis could be a more complex and dynamic process than previously assumed. These findings would be helpful in elucidating the open questions in cell division and cell size heterogeneity.

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