Relevant bibliographies by topics / G2/M checkpoint

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  2. Dissertations / Theses
  3. Book chapters
  4. Conference papers
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Academic literature on the topic 'G2/M checkpoint'

Author: Grafiati
Published: 4 June 2021
Last updated: 15 February 2022

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Journal articles on the topic "G2/M checkpoint"

1

Xu, Bo, Seong-Tae Kim, Dae-Sik Lim, and Michael B. Kastan. "Two Molecularly Distinct G2/M Checkpoints Are Induced by Ionizing Irradiation." Molecular and Cellular Biology 22, no. 4 (2002): 1049–59. http://dx.doi.org/10.1128/mcb.22.4.1049-1059.2002.

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ABSTRACT Cell cycle checkpoints are among the multiple mechanisms that eukaryotic cells possess to maintain genomic integrity and minimize tumorigenesis. Ionizing irradiation (IR) induces measurable arrests in the G1, S, and G2 phases of the mammalian cell cycle, and the ATM (ataxia telangiectasia mutated) protein plays a role in initiating checkpoint pathways in all three of these cell cycle phases. However, cells lacking ATM function exhibit both a defective G2 checkpoint and a prolonged G2 arrest after IR, suggesting the existence of different types of G2 arrest. Two molecularly distinct G2/M checkpoints were identified, and the critical importance of the choice of G2/M checkpoint assay was demonstrated. The first of these G2/M checkpoints occurs early after IR, is very transient, is ATM dependent and dose independent (between 1 and 10 Gy), and represents the failure of cells which had been in G2 at the time of irradiation to progress into mitosis. Cell cycle assays that can distinguish mitotic cells from G2 cells must be used to assess this arrest. In contrast, G2/M accumulation, typically assessed by propidium iodide staining, begins to be measurable only several hours after IR, is ATM independent, is dose dependent, and represents the accumulation of cells that had been in earlier phases of the cell cycle at the time of exposure to radiation. G2/M accumulation after IR is not affected by the early G2/M checkpoint and is enhanced in cells lacking the IR-induced S-phase checkpoint, such as those lacking Nbs1 or Brca1 function, because of a prolonged G2 arrest of cells that had been in S phase at the time of irradiation. Finally, neither the S-phase checkpoint nor the G2 checkpoints appear to affect survival following irradiation. Thus, two different G2 arrest mechanisms are present in mammalian cells, and the type of cell cycle checkpoint assay to be used in experimental investigation must be thoughtfully selected.
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Osman, Fekret, Irina R. Tsaneva, Matthew C. Whitby, and Claudette L. Doe. "UV Irradiation Causes the Loss of Viable Mitotic Recombinants in Schizosaccharomyces pombe Cells Lacking the G2/M DNA Damage Checkpoint." Genetics 160, no. 3 (2002): 891–908. http://dx.doi.org/10.1093/genetics/160.3.891.

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Abstract Elevated mitotic recombination and cell cycle delays are two of the cellular responses to UV-induced DNA damage. Cell cycle delays in response to DNA damage are mediated via checkpoint proteins. Two distinct DNA damage checkpoints have been characterized in Schizosaccharomyces pombe: an intra-S-phase checkpoint slows replication and a G2/M checkpoint stops cells passing from G2 into mitosis. In this study we have sought to determine whether UV damage-induced mitotic intrachromosomal recombination relies on damage-induced cell cycle delays. The spontaneous and UV-induced recombination phenotypes were determined for checkpoint mutants lacking the intra-S and/or the G2/M checkpoint. Spontaneous mitotic recombinants are thought to arise due to endogenous DNA damage and/or intrinsic stalling of replication forks. Cells lacking only the intra-S checkpoint exhibited no UV-induced increase in the frequency of recombinants above spontaneous levels. Mutants lacking the G2/M checkpoint exhibited a novel phenotype; following UV irradiation the recombinant frequency fell below the frequency of spontaneous recombinants. This implies that, as well as UV-induced recombinants, spontaneous recombinants are also lost in G2/M mutants after UV irradiation. Therefore, as well as lack of time for DNA repair, loss of spontaneous and damage-induced recombinants also contributes to cell death in UV-irradiated G2/M checkpoint mutants.
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Xu, Zhiheng, and David Norris. "The SFP1 Gene Product of Saccharomyces cerevisiae Regulates G2/M Transitions During the Mitotic Cell Cycle and DNA-Damage Response." Genetics 150, no. 4 (1998): 1419–28. http://dx.doi.org/10.1093/genetics/150.4.1419.

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Abstract In eukaryotic cells, checkpoint pathways arrest cell-cycle progression if a particular event has failed to complete appropriately or if an important intracellular structure is defective or damaged. Saccharomyces cerevisiae strains that lack the SFP1 gene fail to arrest at the G2 DNA-damage checkpoint in response to genomic injury, but maintain their ability to arrest at the replication and spindle-assembly checkpoints. sfp1Δ mutants are characterized by a premature entrance into mitosis during a normal (undamaged) cell cycle, while strains that overexpress Sfp1p exhibit delays in G2. Sfp1p therefore acts as a repressor of the G2/M transition, both in the normal cell cycle and in the G2 checkpoint pathway. Sfp1 is a nuclear protein with two Cys2His2 zinc-finger domains commonly found in transcription factors. We propose that Sfp1p regulates the expression of gene products involved in the G2/M transition during the mitotic cell cycle and the DNA-damage response. In support of this model, overexpression of Sfp1p induces the expression of the PDS1 gene, which is known to encode a protein that regulates the G2 checkpoint.
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Qiu, Ling, Andrew Burgess, David P. Fairlie, Helen Leonard, Peter G. Parsons, and Brian G. Gabrielli. "Histone Deacetylase Inhibitors Trigger a G2 Checkpoint in Normal Cells That Is Defective in Tumor Cells." Molecular Biology of the Cell 11, no. 6 (2000): 2069–83. http://dx.doi.org/10.1091/mbc.11.6.2069.

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Important aspects of cell cycle regulation are the checkpoints, which respond to a variety of cellular stresses to inhibit cell cycle progression and act as protective mechanisms to ensure genomic integrity. An increasing number of tumor suppressors are being demonstrated to have roles in checkpoint mechanisms, implying that checkpoint dysfunction is likely to be a common feature of cancers. Here we report that histone deacetylase inhibitors, in particular azelaic bishydroxamic acid, triggers a G2 phase cell cycle checkpoint response in normal human cells, and this checkpoint is defective in a range of tumor cell lines. Loss of this G2 checkpoint results in the tumor cells undergoing an aberrant mitosis resulting in fractured multinuclei and micronuclei and eventually cell death. This histone deacetylase inhibitor-sensitive checkpoint appears to be distinct from G2/M checkpoints activated by genotoxins and microtubule poisons and may be the human homologue of a yeast G2 checkpoint, which responds to aberrant histone acetylation states. Azelaic bishydroxamic acid may represent a new class of anticancer drugs with selective toxicity based on its ability to target a dysfunctional checkpoint mechanism in tumor cells.
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Xu, Bo, Seong-tae Kim, and Michael B. Kastan. "Involvement of Brca1 in S-Phase and G2-Phase Checkpoints after Ionizing Irradiation." Molecular and Cellular Biology 21, no. 10 (2001): 3445–50. http://dx.doi.org/10.1128/mcb.21.10.3445-3450.2001.

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ABSTRACT Cell cycle arrests in the G1, S, and G2phases occur in mammalian cells after ionizing irradiation and appear to protect cells from permanent genetic damage and transformation. Though Brca1 clearly participates in cellular responses to ionizing radiation (IR), conflicting conclusions have been drawn about whether Brca1 plays a direct role in cell cycle checkpoints. Normal Nbs1 function is required for the IR-induced S-phase checkpoint, but whether Nbs1 has a definitive role in the G2/M checkpoint has not been established. Here we show that Atm and Brca1 are required for both the S-phase and G2 arrests induced by ionizing irradiation while Nbs1 is required only for the S-phase arrest. We also found that mutation of serine 1423 in Brca1, a target for phosphorylation by Atm, abolished the ability of Brca1 to mediate the G2/M checkpoint but did not affect its S-phase function. These results clarify the checkpoint roles for each of these three gene products, demonstrate that control of cell cycle arrests must now be included among the important functions of Brca1 in cellular responses to DNA damage, and suggest that Atm phosphorylation of Brca1 is required for the G2/M checkpoint.
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Dhar, Sonu, Jeremy A. Squire, M. Prakash Hande, Raymund J. Wellinger та Tej K. Pandita. "Inactivation of 14-3-3ς Influences Telomere Behavior and Ionizing Radiation-Induced Chromosomal Instability". Molecular and Cellular Biology 20, № 20 (2000): 7764–72. http://dx.doi.org/10.1128/mcb.20.20.7764-7772.2000.

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ABSTRACT Telomeres are complexes of repetitive DNA sequences and proteins constituting the ends of linear eukaryotic chromosomes. While these structures are thought to be associated with the nuclear matrix, they appear to be released from this matrix at the time when the cells exit from G2 and enter M phase. Checkpoints maintain the order and fidelity of the eukaryotic cell cycle, and defects in checkpoints contribute to genetic instability and cancer. The 14-3-3ς gene has been reported to be a checkpoint control gene, since it promotes G2 arrest following DNA damage. Here we demonstrate that inactivation of this gene influences genome integrity and cell survival. Analyses of chromosomes at metaphase showed frequent losses of telomeric repeat sequences, enhanced frequencies of chromosome end-to-end associations, and terminal nonreciprocal translocations in 14-3-3ς−/− cells. These phenotypes correlated with a reduction in the amount of G-strand overhangs at the telomeres and an altered nuclear matrix association of telomeres in these cells. Since the p53-mediated G1 checkpoint is operative in these cells, the chromosomal aberrations observed occurred preferentially in G2 after irradiation with gamma rays, corroborating the role of the 14-3-3ς protein in G2/M progression. The results also indicate that even in untreated cycling cells, occasional chromosomal breaks or telomere-telomere fusions trigger a G2 checkpoint arrest followed by repair of these aberrant chromosome structures before entering M phase. Since 14-3-3ς−/− cells are defective in maintaining G2 arrest, they enter M phase without repair of the aberrant chromosome structures and undergo cell death during mitosis. Thus, our studies provide evidence for the correlation among a dysfunctional G2/M checkpoint control, genomic instability, and loss of telomeres in mammalian cells.
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Meng, Xiangbing, Jianling Bi, Yujun Li, et al. "AZD1775 Increases Sensitivity to Olaparib and Gemcitabine in Cancer Cells with p53 Mutations." Cancers 10, no. 5 (2018): 149. http://dx.doi.org/10.3390/cancers10050149.

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Tumor suppressor p53 is responsible for enforcing cell cycle checkpoints at G1/S and G2/M in response to DNA damage, thereby allowing both normal and tumor cells to repair DNA before entering S and M. However, tumor cells with absent or mutated p53 are able to activate alternative signaling pathways that maintain the G2/M checkpoint, which becomes uniquely critical for the survival of such tumor cells. We hypothesized that abrogation of the G2 checkpoint might preferentially sensitize p53-defective tumor cells to DNA-damaging agents and spare normal cells with intact p53 function. The tyrosine kinase WEE1 regulates cdc2 activity at the G2/M checkpoint and prevents entry into mitosis in response to DNA damage or stalled DNA replication. AZD1775 is a WEE1 inhibitor that overrides and opens the G2/M checkpoint by preventing WEE1-mediated phosphorylation of cdc2 at tyrosine 15. In this study, we assessed the effect of AZD1775 on endometrial and ovarian cancer cells in the presence of two DNA damaging agents, the PARP1 inhibitor, olaparib, and the chemotherapeutic agent, gemcitabine. We show that AZD1775 alone is effective as a therapeutic agent against some p53 mutated cell models. Moreover, the combination of AZD1775 with olaparib or gemcitabine is synergistic in cells with mutant p53 and constitutes a new approach that should be considered in the treatment of advanced and recurrent gynecologic cancer.
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Kumar, Subodh, Srikanth Talluri, Mariateresa Fulciniti, Masood A. Shammas, and Nikhil C. Munshi. "Elevated APEX1 Disrupts G2/M Checkpoint, Contributing to Evolution and Survival of Myeloma Cells." Blood 126, no. 23 (2015): 2997. http://dx.doi.org/10.1182/blood.v126.23.2997.2997.

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Abstract Cell cycle checkpoints provide the cell with time to repair chromosomal DNA damage before its replication (G1) and also prior to its segregation (G2), thus ensuring integrity, maintenance and protection of genome. Although proper functioning of both checkpoints is essential, G2/M has a special significance as a potentially lethal double-strand break in DNA escape repair and persist from G2 into mitosis, it may recombine in G1 to produce gene rearrangements. Moreover, G2 is the phase where homologous recombination (HR) can utilize a sister chromatid as a template to provide error-free repair. There is ample evidence that supports the role of defective G2/M checkpoint and dysregulated HR in genomic rearrangements and evolution in cancer. Previously, we have shown that elevated APEX1 contributes to dysregulated HR and genome stability in multiple myeloma (MM), and its upregulation leads to genomic instability and tumorigenesis in animal model. To further understand the role of APEX1 in myeloma, we investigated the impact of elevated APEX1 on cell cycle checkpoint/s and in the cellular response to genotoxic exposure. Our investigation using antibody array and subsequent confirmation with immunoprecipitation experiments demonstrated that APEX1 interacts with cyclin B and PLK in myeloma cells. A key step in progression from G2 to mitosis is the activation of cyclin B-CDK1 complex, which subsequently activates PLK to ensure G2/M progression. Based on observed interaction of APEX1 with cyclin B/PLK, we hypothesized that elevated APEX1 disrupts G2 checkpoint by mediating progression into mitosis. To test this, we inhibited APEX1 in myeloma cells by a small molecule as well as by shRNA targeting this gene, and investigated the impact on cell cycle checkpoints using a unique phospho-antibody array which allows investigation of 238 relevant proteins and their phosphorylation status. APEX1 inhibition by small molecule led to downregulation (> 2-fold) of many proteins/phosphorylations involved in the activation of cyclin B-CDK1 complex and other mediators of G2/M progression (including CDC25A, CDC25A, CDK1, ABL1), and upregulation of proteins/phosphorylations involved in G2/M arrest, including CDK1-phospho-Tyr15, 14-3-3 zeta-phospho-Ser58, p53-phospho-Ser15, and MYT and WEE which are involved in negative regulation of cyclin B-CDK1 complex. To further investigate the role of APEX1 in G2/M progression, myeloma cell lines (ARP, RPMI 8226, MM1S, LR5, H929) were treated with APEX1 inhibitor and subjected to cell cycle analysis using flow cytometery. Compared to control cells, all five APEX1-inhibitor treated cell lines showed a strong G2/M block, ranging from 5- to 10-fold increase in the fraction of cells in G2 phase in a dose dependent manner. The G2/M cell cycle arrest of APEX1-treated myeloma cells was further supported by reduced cell viability of treated myeloma cells (RPMI, H929, MM1S, ARP and U266); IC50 of inhibitor in myeloma cell lines ranged from 1.2 to 4 µM. Co-treatment with APEX1 inhbitor also sensitized myeloma cells to Melphalan. Consistent with these data, shRNA-mediated knockdown (KD) of APEX1 in RPMI cells was associated with 4-fold increase in the fraction of cells in G2, relative to control cells. APEX1-KD was also associated with reduction in cell viability (by 40%) and sensitization to melphalan. Our results therefore suggest that elevated APEX1 disrupts G2 checkpoint and sets a stage for genomic rearrangements by allowing persistance of DNA damage from G2 into mitosis. Dysfunctional G2 checkpoint, combined with APEX1-mediated dysregulation of HR, could be attributed to APEX1 associated genomic instability and oncogenic transformation. Therefore, inhibitors of APEX1, alone or in combination with other agents, have potential to make myeloma cells static. Disclosures No relevant conflicts of interest to declare.
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Naiki, Takahiro, Toshiyasu Shimomura, Tae Kondo, Kunihiro Matsumoto, and Katsunori Sugimoto. "Rfc5, in Cooperation with Rad24, Controls DNA Damage Checkpoints throughout the Cell Cycle inSaccharomyces cerevisiae." Molecular and Cellular Biology 20, no. 16 (2000): 5888–96. http://dx.doi.org/10.1128/mcb.20.16.5888-5896.2000.

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ABSTRACT RAD24 and RFC5 are required for DNA damage checkpoint control in the budding yeast Saccharomyces cerevisiae. Rad24 is structurally related to replication factor C (RFC) subunits and associates with RFC subunits Rfc2, Rfc3, Rfc4, and Rfc5. rad24Δ mutants are defective in all the G1-, S-, and G2/M-phase DNA damage checkpoints, whereas the rfc5-1 mutant is impaired only in the S-phase DNA damage checkpoint. Both the RFC subunits and Rad24 contain a consensus sequence for nucleoside triphosphate (NTP) binding. To determine whether the NTP-binding motif is important for Rad24 function, we mutated the conserved lysine115 residue in this motif. The rad24-K115E mutation, which changes lysine to glutamate, confers a complete loss-of-function phenotype, while the rad24-K115R mutation, which changes lysine to arginine, shows no apparent phenotype. Although neitherrfc5-1 nor rad24-K115R single mutants are defective in the G1- and G2/M-phase DNA damage checkpoints, rfc5-1 rad24-K115R double mutants become defective in these checkpoints. Coimmunoprecipitation experiments revealed that Rad24K115R fails to interact with the RFC proteins in rfc5-1 mutants. Together, these results indicate that RFC5, like RAD24, functions in all the G1-, S- and G2/M-phase DNA damage checkpoints and suggest that the interaction of Rad24 with the RFC proteins is essential for DNA damage checkpoint control.
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Furnari, Beth, Alessandra Blasina, Michael N. Boddy, Clare H. McGowan, and Paul Russell. "Cdc25 Inhibited In Vivo and In Vitro by Checkpoint Kinases Cds1 and Chk1." Molecular Biology of the Cell 10, no. 4 (1999): 833–45. http://dx.doi.org/10.1091/mbc.10.4.833.

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In the fission yeast Schizosaccharomyces pombe, the protein kinase Cds1 is activated by the S–M replication checkpoint that prevents mitosis when DNA is incompletely replicated. Cds1 is proposed to regulate Wee1 and Mik1, two tyrosine kinases that inhibit the mitotic kinase Cdc2. Here, we present evidence from in vivo and in vitro studies, which indicates that Cds1 also inhibits Cdc25, the phosphatase that activates Cdc2. In an in vivo assay that measures the rate at which Cdc25 catalyzes mitosis, Cds1 contributed to a mitotic delay imposed by the S–M replication checkpoint. Cds1 also inhibited Cdc25-dependent activation of Cdc2 in vitro. Chk1, a protein kinase that is required for the G2–M damage checkpoint that prevents mitosis while DNA is being repaired, also inhibited Cdc25 in the in vitro assay. In vitro, Cds1 and Chk1 phosphorylated Cdc25 predominantly on serine-99. The Cdc25 alanine-99 mutation partially impaired the S–M replication and G2–M damage checkpoints in vivo. Thus, Cds1 and Chk1 seem to act in different checkpoint responses to regulate Cdc25 by similar mechanisms.
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Dissertations / Theses on the topic "G2/M checkpoint"

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Tao, Yungan. "Interruption of G2-M and mitotic checkpoint : Influence on tumor radiosensitivity." Paris 11, 2008. http://www.theses.fr/2008PA11T062.

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Thanasoula, Maria. "ATM/ATR-dependent responses to dysfunctional telomeres at the G2/M transition." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:b9f806e3-88e5-4dc4-b2e9-8ecf854249d1.

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Mammalian telomeres are nucleoprotein complexes at the end of chromosomes containing a specific protein complex, called shelterin. Shelterin protects chromosome ends from the DNA damage response (DDR), by facilitating the formation of a telomeric capping structure, called the T-loop. During their elongation in S phase, telomeres become transiently uncapped and can be sensed as DNA damage in G2 phase. This leads to the recruitment of DDR factors, such as phosphorylated histone H2AX (γH2AX), to the telomeres forming the so-called, telomere dysfunction-induced foci (TIFs). My PhD work described here, indicates that DNA damage occurring during interphase can persist after entry into mitosis, indicated by the detection of γH2AX at a subset of mitotic telomeres in human and mouse cells. This accumulation of γH2AX to mitotic telomeres is ATM-dependent and the γH2AX-labelled uncapped telomeres that persist, are shorter than the average telomere length for the entire cell population. Most importantly, my work suggests that telomere uncapping, naturally occurring or artificially induced, is detected by two parallel ATM/ATR-dependent pathways at the G2/M transition: a p53/p21-dependent pathway through the ATM/ATR-mediated phosphorylation of p53 at Ser15 and a CHK1/CHK2-dependent pathway that acts through negative regulation of CDC25 phosphatases. In particular, telomere uncapping triggered by TRF2 depletion leads to CHK2-dependent CDC25A degradation, while POT1 depletion results in CHK1-mediated CDC25A and CDC25C degradation. Both pathways act as sensors of unprotected telomeres at the G2/M transition and block cell cycle progression through inhibition of CDK1/Cyclin B complex, allowing telomere re-capping before entry into mitosis. This mechanism protects telomere integrity by the maintenance of a cell cycle stage conducive for capping reactions and thereby prevents genomic instability induced by telomere dysfunction. Finally, I studied the cellular functions of 3 poorly characterised shelterin components, TRF1, RAP1 and TPP1, in telomere protection. TRF1 and to a lesser extent RAP1 were shown to be important for telomere protection by suppressing DDR at the telomeres, while TPP1 was shown to be mainly responsible for the recruitment of the catalytic subunit of telomerase, TERT , to the chromatin, contributing to telomere maintenance. In conclusion, my work on both human and mouse models, reveals an important part of the DDR pathways activated by dysfunctional telomeres, as well as the molecular mechanisms underlying the cell cycle specific regulation of telomere capping, which ensures that only cells with intact telomeres enter mitosis.
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Cervigni, Romina Ines. "Analysis of the molecular mechanisms of the Golgi-based G2/M cell cycle checkpoint." Thesis, Open University, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.580685.

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This thesis is focused on the role of Golgi fragmentation in the regulation of the G2/M transition of the cell cycle, and it is based on previous findings that Golgi fragmentation is required to enter into mitosis. The Golgi complex is composed of many cisternal stacks that are interconnected by tubules, to form a continuous 'ribbon-like' structure. During mitosis, the Golgi ribbon undergoes extensive fragmentation through a multi stage process that promotes its correct partitioning and inheritance by the daughter cells. The first part of my work is focused on the understanding of the mechanisms which block cells in G2 when Golgi fragmentation is inhibited. I show that the Golgi-dependent G2 arrest is mediated by a failure of centrosome maturation, an event that is essential to achieve activation of the CdkllCyclinB (Cdkl/CycB) complex, the master regulator of mitosis. Indeed, the failure of Golgi fragmentation inhibits the recruitment to and activation at the centrosome of the kinase Aurora-A. This kinase is essential for the activation of Cdkl/CycB at the centrosome. This part of the thesis contributes to the definition of a previously unidentified point of dialogue between the Golgi apparatus and the centrosome in the regulation of G2/M transition. The second part of the thesis describes the development of three novel experimental approaches to induce the block of Golgi fragmentation. They integrate a previously developed assay that is based on the microinjection of blockers of Golgi fragmentation, a reliable but demanding approach. The assays that I have developed are based on the ability of the GRASP65 protein to regulate Golgi fragmentation. As well as being essential for inducing the Golgi checkpoint in a wide cell population, they are also useful for the unravelling of the mechanism through which GRASP65 acts in the Golgi checkpoint.
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Feeney, Katherine M. "Investigations of G2/M decatenation checkpoint control, using the DNA topoisomerase II inhibitor ICRF-193." Thesis, University of Ulster, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.529562.

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Putnam, Charles Wellington. "Integration of G2/M checkpoint, spindle assembly checkpoint,and Ran cycle regulators in the Saccharomyces cerevisiae DNA damage mitotic arrest response." Diss., The University of Arizona, 2004. http://hdl.handle.net/10150/280738.

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It is axiomatic that genomic stability is dependent upon regulatory pathways, termed checkpoints, which sense perturbations of cell cycle execution including damage to chromosomal DNA. In Saccharomyces cerevisiae, the principal DNA damage checkpoint is at G2/M. Heretofore, this and other checkpoints, such as the spindle assembly checkpoint, which is also operative at the metaphase/anaphase transition, have been viewed as essentially linear pathways, responding to a specific type of damage, signaling via sui generis proteins, and targeting a limited number of effectors for arrest. In a 1999 report, our laboratory reported bifurcation of the pathway downstream from Mec1 activation; this established the genetic basis of a previously unexplained phenotype: partial arrest defects of rad53 and pds1 strains. Moreover, the bifurcated pathway model established the framework for subsequent studies which determined the molecular targets of each. Here, I present evidence that the DNA damage and spindle checkpoint pathways are part of a network which is capable of bilaterally responding to damage. After DNA damage the Mec1-centric pathway is initially preeminent; the spindle pathway is redundant. After prolonged damage, however, the spindle checkpoint components become required for arrest. In studies of overexpression of the Mec1 homologue Tel1, I delineated the pathway responsible for the resultant constitutive delay; strikingly, the spindle components Mad1 and Mad2 are activated, not from the kinetochore, but from the nuclear periphery. This off-kinetochore pool of Mad proteins, anchored by the myosin-like proteins, Mlp1 and Mlp2, is likewise activated by the DNA damage response. Tel1 physically interacts with Xrs2 of the Mre11·Rad50·Xrs2 complex; evidence that Xrs2 participates in these same responses is also presented. Finally, the sensitivity of xrs2 to a microtubule poison, benomyl, suggests that M R·X may also participate in sensing spindle disruption. From a screen for novel checkpoint genes, I isolated Gtr1 (and later, Gtr2), which are negative regulators of the Ran cycle. Here, I provide evidence that deletion of either produces an identical partial arrest defect, which is independent of the Mec1-centric pathway. Because Gtr2 physically interacts with Esp1, I surmise that Gtr1/Gtr2 may enforce cytosolic localization of Pds1/Esp1 after DNA damage.
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McKenzie, Lynsey. "G2/M checkpoint associated repression of polo-like kinase-1 mediated by the tumour suppressor, p53." Thesis, University of Dundee, 2010. https://discovery.dundee.ac.uk/en/studentTheses/fea09569-1f92-4084-8dbe-d85de3c86c6d.

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Polo-like Kinase-1 (PLK1) is an important mediator of the G2/M phase of the cell cycle that is down-regulated in a DNA damage dependent manner. In cancer cells PLK1 is overexpressed and allows for continued proliferation of the cell by overriding this checkpoint. Here I show that PLK1 is down-regulated in a p53-dependent manner and that can occur both in response to DNA damage and to a non-genotoxic stimulus of the p53 pathway. My data show that p53 is able to repress PLK1 through a responsive element in the promoter and that p53 is necessary and sufficient to cause PLK1 repression. When examined in the context of a PLK1 promoter/reporter fusion, wild type but not mutated forms of p53 can repress expression. EMSA shows that p53 binds to the p53-responsive element and that mutation of this element reduces p53 binding. Furthermore, PLK1 repression occurs independently of p21-mediated arrest at G1/S, a stage of the cell cycle where PLK1 levels are physiologically low. PLK1 repression mediated by p21 through the CDE/CHR element in the promoter does not appear to cause significant repression of PLK1 but may play a minor role. Down-regulation of PLK1 is relieved by the HDAC inhibitor TSA and supports the transcriptional repression mechanism described in this thesis. Silencing of PLK1 expression by siRNA interferes with cell cycle progression consistent with a role in the p53-mediated checkpoint. This thesis provides two distinct and perhaps overlapping mechanisms by which p53 may repress PLK1: 1)through competitive displacement of an unidentified transcription factor that is essential for normal PLK1 expression and 2) through HDAC recruitment leading to local repression-associated changes in the chromatin structure. These data establish PLK1 as a transcriptional target of p53 that is required for efficient G2/M arrest.
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Beckta, Jason. "ATM, BRCA1, and Aurora A: Mechanisms of G2/M Checkpoint Control in Human Embryonic Stem Cells." VCU Scholars Compass, 2014. http://scholarscompass.vcu.edu/etd/3477.

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When cultured in vitro, human embryonic stem cells (hESCs) acquire genetic abnormalities that have slowed their therapeutic use. As hESCs have a “leaky” G1/S boundary, the pressure of ensuring genetic integrity falls on the G2/M checkpoint, which can be activated by failed chromosomal decatenation (among other stimuli). It is hypothesized that hESCs have a deficient decatenation checkpoint, but little data supports this. Evidence suggests that the ataxia telangiectasia mutated (ATM) kinase controls the G2/M decatenation and DNA damage checkpoints, though previous reports are conflicting on this point. My work demonstrates that inhibition of decatenation activates ATM and arrests hESCs in G2. Pharmacologic inhibition of ATM (ATMi) abrogates this arrest, allowing hESCs to enter mitosis. Live cell imaging studies reveal that ATMi increases the time it takes to complete mitosis. Culture of cells under ATMi causes a gain of DNA content, which is reversed once ATMi is relieved. BRCA1, a known target of ATM, is also involved in the G2/M checkpoint. Experimental evidence reveals that activated ATM phosphorylates BRCA1, preventing Aurora A from interacting with and phosphorylating BRCA1 on S308, a modification necessary for mitotic entry. Together, this data illuminates a novel pathway by which ATM activation mediates G2 arrest in hESCs.
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Huang, Yehong. "The Kinetics of G2 and M Transitions Regulated by B Cyclins." Case Western Reserve University School of Graduate Studies / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=case1386197228.

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Brunton, Holly. "Investigating the role of higher order chromatin structure and DNA damage complexity on ATM signalling and G2/M checkpoint arrest." Thesis, University of Sussex, 2011. http://sro.sussex.ac.uk/id/eprint/7166/.

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In response to DNA double stranded breaks (DSBs), mammalian cells have evolved two major repair pathways, DNA Non Homologous End Joining (NHEJ) and Homologous Recombination (HR). The majority of DSB repair in G1 and G2 phase is repaired with fast kinetics by NHEJ in a pathway that involves the core NHEJ factors: Ku, DNA-PKcs, XLF, DNA Ligase IV and XRCC4. A subset of slow repairing DSBs also requires ATM and Artemis (Riballo et al, 2004). This slow component of repair represents DSBs that reside within highly compacted regions of the genome known as heterochromatin (HC) (Goodarzi et al, 2008). ATM functions at HC to mediate relaxation by phosphorylating the HC building factor KAP-1 (Goodarzi et al, 2008). Here I provide evidence that DSBs dependent upon Artemis for their repair also reside within regions of HC. However, unlike ATM, Artemis functions downstream of the HC relaxation process. In response to DSBs, ATM phosphorylates the histone variant H2AX (γH2AX). γH2AX acts as a docking site for the localized recruitment and activation of DNA Damage Response (DDR) proteins. The expansion of γH2AX can spread over megabases of DNA. Here I have shown that highly compacted KAP-1, MeCP2 and DNMT3B enriched chromatin acts as a barrier to IR induced γH2AX expansion. In patient cells deficient for MeCP2 or DNMT3B proteins, such as Rett syndrome (MeCP2 deficient) and Immunodeficiency centromeric-instability facial-anomalies syndrome (DNMT3B deficient), ATM and Chk2 signalling is heightened, which is reflected in a hypersensitive and prolonged G2/M checkpoint arrest. These findings suggest that higher order chromatin complexity is a barrier to ATM signalling to the checkpoint machinery. In the final section of my thesis, I addressed what affect DNA damage complexity exerts on checkpoint arrest. Using exposure to heavy ion irradiation, which induces complex DSBs, I observed larger γH2AX foci and prolonged G2/M checkpoint arrest.
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Bose, M. (Muthiah). "Molecular and functional characterization of ABRAXAS and PALB2 genes in hereditary breast cancer predisposition." Doctoral thesis, Oulun yliopisto, 2019. http://urn.fi/urn:isbn:9789526218656.

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Abstract Hereditary mutations in DNA damage response (DDR) genes often lead to genomic instability and ultimately tumor development. However, the molecular mechanism of how these DDR deficiencies promote genomic instability and malignancy is not well understood. Thus, the specific aim of this thesis is to identify the functional and molecular framework behind the elevated breast cancer risk observed in heterozygous PALB2 and ABRAXAS mutation carriers. The heterozygous germline alteration in PALB2 (c.1592delT) causes a haploinsufficiency phenotype in the mutation carrier cells. Due to PALB2 haploinsufficiency, elevated Cdk activity and consequently aberrant DNA replication/damage response was observed in the PALB2 mutation carrier cells. Excessive origin firing that is indicative of replication stress was also seen in the PALB2 mutation carrier cells. In addition to replication stress, PALB2 mutation carrier cells also experience G2/M checkpoint maintenance defects. The increased malignancy risk in females associated with heterozygosity for the Finnish PALB2 founder mutation is likely to be due to aberrant DNA replication, elevated genomic instability and multiple different cell cycle checkpoint defects. The heterozygous germline alteration in ABRAXAS (c.1082G&#62;A) causes a dominant-negative phenotype in the mutation carrier cells. Decreased BRCA1 protein levels as well as reduced nuclear localization and foci formation of BRCA1 and CtIP was observed in the ABRAXAS mutation carrier cells. This causes disturbances in basal BRCA1-A complex localization, which is reflected by a restraint in error-prone DNA double-strand break (DSB) repair pathway usage, attenuated DNA damage response, deregulated G2/M checkpoint control and apoptosis. Most importantly, mutation carrier cells display a change in their transcriptional profile, which we attribute to the reduced nuclear levels of BRCA1. Thus, the Finnish ABRAXAS founder mutation acts in a dominant-negative manner on BRCA1 to promote genome destabilization in the heterozygous carrier cells<br>Tiivistelmä Perinnölliset muutokset DNA-vauriovasteen geeneissä johtavat usein genomin epävakauteen ja lopulta syövän kehittymiseen. Molekyylitason mekanismeja, joilla vauriovasteen vajaatoiminta ajaa genomin epävakautta ja syöpää, ei kuitenkaan ymmärretä kunnolla. Tämän väitöskirjan tavoitteena on tunnistaa solutoiminnan ja molekyylitason vaikuttajat heterotsygoottisten PALB2- ja ABRAXAS-geenimuutosten kantajien kohonneen rintasyöpäriskin taustalla. Heterotsygoottinen ituradan suomalainen perustajamuutos PALB2-geenissä (c.1592delT) aiheuttaa haploinsuffisienssin kantajahenkilöiden soluissa. PALB2:n haploinsuffisienssin seurauksena kantajasoluissa havaittiin kohonnutta Cdk-proteiinin aktiivisuutta ja siitä johtuvaa kiihtynyttä DNA:n kahdentumista. PALB2-mutaatiota kantavissa soluissa nähtiin myös liiallista replikaation aloituskohtien käyttöä, mikä viittaa replikaatiostressiin. Replikaatiostressin lisäksi PALB2-mutaation kantajasoluilla havaittiin vaikeuksia ylläpitää solusyklin G2/M-tarkastuspisteen toimintaa. Näiden solutoiminnan poikkeavuuksien takia heterotsygoottisen PALB2 c.1592delT -mutaation kantajilla todettiin genomin epävakautta ja kohonnut syöpäriski. Heterotsygoottinen ituradan mutaatio ABRAXAS-geenissä (c.1082G&#62;A) aiheuttaa dominantti-negatiivisen fenotyypin mutaation kantajasoluissa. ABRAXAS-mutaatiota kantavissa soluissa havaittiin BRCA1-proteiinitasojen laskua sekä BRCA1- ja CtIP-proteiinien vähentynyttä lokalisaatiota tumaan ja DNA-vauriopaikoille. Tämä aiheuttaa häiriöitä BRCA1-A-kompleksin paikallistumisessa, mikä johtaa häiriöihin virhealttiiden DNA-kaksoisjuoste¬katkoksien korjausmekanismien käytössä, DNA-vauriovasteessa, G2/M-tarkastus-pisteen säätelyssä ja ohjelmoidussa solukuolemassa. Tärkeimpänä löydöksenä havaittiin mutaation kantajasoluissa muuttunut transkriptioprofiili, joka johtunee BRCA1-proteiinitasojen laskusta tumassa. Näin ollen suomalainen ABRAXAS-perustajamutaatio toimii dominantti-negatiivisena BRCA1:n suhteen, aiheuttaen genomin epävakautta heterotsygoottisissa kantajasoluissa
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Book chapters on the topic "G2/M checkpoint"

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Ye, Xiang S., and Stephen A. Osmani. "Regulation of p34cdc2/cylinB H1 and NIMA kinases during the G2/M transition and checkpoint responses in Aspergillus nidulans." In Progress in Cell Cycle Research. Springer US, 1997. http://dx.doi.org/10.1007/978-1-4615-5371-7_17.

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"G2/M Checkpoint." In Encyclopedia of Cancer. Springer Berlin Heidelberg, 2011. http://dx.doi.org/10.1007/978-3-642-16483-5_2466.

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Fasullo, Michael. "Checkpoint Control of DNA Repair in Yeast." In Saccharomyces. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.96966.

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Budding yeast has been a model organism for understanding how DNA damage is repaired and how cells minimize genetic instability caused by arresting or delaying the cell cycle at well-defined checkpoints. However, many DNA damage insults are tolerated by mechanisms that can both be error-prone and error-free. The mechanisms that tolerate DNA damage and promote cell division are less well-understood. This review summarizes current information known about the checkpoint response to agents that elicit both the G2/M checkpoint and the intra-S phase checkpoint and how cells adapt to unrepaired DNA damage. Tolerance to particular bulky DNA adducts and radiomimetic agents are discussed, as well as possible mechanisms that may control phosphatases that deactivate phosphorylated proteins.
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Conference papers on the topic "G2/M checkpoint"

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Li, G., S. S. Nair, S. J. Lees, and F. W. Booth. "Regulation of G2/M Transition in Mammalian Cells by Oxidative Stress." In ASME 2005 International Mechanical Engineering Congress and Exposition. ASMEDC, 2005. http://dx.doi.org/10.1115/imece2005-82349.

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The regulation of the G2/M transition for the mammalian cell cycle has been modeled using 19 states to investigate the G2 checkpoint dynamics in response to oxidative stress. A detailed network model of G2/M regulation is presented and then a “core” subsystem is extracted from the full network. An existing model of Mitosis control is extended by adding two important pathways regulating G2/M transition in response to DNA damage induced by oxidative stress. Model predictions indicate that the p53 dependent pathway is not required for initial G2 arrest as the Chk1/Cdc25C pathway can arrest the cell in G2 right after DNA damage. However, p53 and p21 expression is important for a more sustained G2 arrest by inhibiting the Thr161 phosphorylation by CAK. By eliminating the phosphorylation effect of Chk1 on p53, two completely independent pathways are obtained and it is shown that it does not affect the G2 arrest much. So the p53/p21 pathway makes an important, independent contribution to G2 arrest in response to oxidative stress, and any defect in this pathway may lead to genomic instability and predisposition to cancer. Such strict control mechanisms probably provide protection for survival in the face of various environmental changes. The controversial issue related to the mechanism of inactivation of Cdc2 by p21 is addressed and simulation predictions indicate that G2 arrest would not be affected much by considering the direct binding of p21 to Cdc2/Cyclin B given that the inhibition of CAK by p21 is already present if the binding efficiency is within a certain range. Lastly, we show that the G2 arrest time in response to oxidative stress is sensitive to the p53 synthesis rate.
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Rorà, Andrea Ghelli Luserna di, Ilaria Iacobucci, Enrica Imbrogno, et al. "Abstract 294: Override the doxorubicin-induced G2/M checkpoint using cell-cycle checkpoint inhibitors on acute lymphoblastic leukemia." In Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.am2017-294.

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Simhadri, Srilatha R., Hong Cai, and Bing Xia. "Abstract 636: Role of PALB2 and the BRCA complex in G2/M checkpoint control." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-636.

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Gery, Sigal, Takayuki Tabasyhi, Verena Nowak, Rocio Alvarez, Julia Sohn, and Phillip H. Koeffler. "Abstract 3871: Per1 is phosphorylated by ATM/ATR and is involved in the G2/M checkpoint response." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-3871.

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Parsels, Leslie A., Daria M. Tanska, Joshua D. Parsels, et al. "Abstract 2964: AZD7762-mediated gemcitabine sensitization does not require G2-M checkpoint abrogation in pancreatic cancer cells." In Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1538-7445.am2011-2964.

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Ghosh-Choudhury, Triparna, Holli A. Loomans, Ying-Wooi Wan, Zhangdon Liu, Shannon M. Hawkins, and Matthew L. Anderson. "Abstract 3113: Hyperactivation of FOXM1 drives ovarian cancer growth and metastasis independent of the G2-M cell cycle checkpoint." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-3113.

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Chatterjee, Suman, and Timothy F. Burns. "Abstract 762: Ganetespib resistance inKRASmutant NSCLC is mediated through bypassing the G2/M checkpoint and reactivating the PI3K/MTOR pathway." In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-762.

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Chen, Ke, Kongming Wu, Wei Zhang, et al. "Abstract LB-144: A p53-dependent G2/M checkpoint governed by the cell-fate factor dachshund in non-small cell lung cancer." In Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-lb-144.

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Yan, Ying, Patrick M. Greer, Ryan H. Kolb, and Kenneth H. Cowan. "Abstract 2041: Her2/Neu has an essential role for the gamma-irradiation-induced ERK1/2 signaling activation and G2/M checkpoint response." In Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-2041.

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Sen, Triparna, Pan Tong, Catherine Allison Stewart, et al. "Abstract PR10: Exploiting the G2-M cell cycle checkpoint dependency in small cell lung cancer (SCLC) using pharmacological inhibitors of CHK1 and WEE1." In Abstracts: AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; February 28 - March 2, 2016; Orlando, FL. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1557-3125.cellcycle16-pr10.

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Reports on the topic "G2/M checkpoint"

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Hall, Eric J., Lubomir B. Smilenov, and Erik F. Young. Genetic Control of the Trigger for the G2/M Checkpoint. Office of Scientific and Technical Information (OSTI), 2013. http://dx.doi.org/10.2172/1095188.

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Oesterreich, Steffi. The Scaffold Attachment Factor SAFB1P: A New Player in G2/M Checkpoint Control. Defense Technical Information Center, 2005. http://dx.doi.org/10.21236/ada435280.

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McGowan, Clare H. The Role of G2/M Checkpoint Controls in Cytotoxic Treatment of Breast Cancer. Defense Technical Information Center, 1997. http://dx.doi.org/10.21236/ada340581.

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