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Journal articles on the topic 'DNA damage checkpoint'

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Published: 4 June 2021
Last updated: 10 March 2023

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1

Heideker, Johanna, Ewa T. Lis, and Floyd E. Romesberg. "Phosphatases, DNA Damage Checkpoints and Checkpoint Deactivation." Cell Cycle 6, no. 24 (December 15, 2007): 3058–64. http://dx.doi.org/10.4161/cc.6.24.5100.

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2

Bashkirov, Vladimir I., Jeff S. King, Elena V. Bashkirova, Jacqueline Schmuckli-Maurer, and Wolf-Dietrich Heyer. "DNA Repair Protein Rad55 Is a Terminal Substrate of the DNA Damage Checkpoints." Molecular and Cellular Biology 20, no. 12 (June 15, 2000): 4393–404. http://dx.doi.org/10.1128/mcb.20.12.4393-4404.2000.

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ABSTRACT Checkpoints, which are integral to the cellular response to DNA damage, coordinate transient cell cycle arrest and the induced expression of DNA repair genes after genotoxic stress. DNA repair ensures cellular survival and genomic stability, utilizing a multipathway network. Here we report evidence that the two systems, DNA damage checkpoint control and DNA repair, are directly connected by demonstrating that the Rad55 double-strand break repair protein of the recombinational repair pathway is a terminal substrate of DNA damage and replication block checkpoints. Rad55p was specifically phosphorylated in response to DNA damage induced by the alkylating agent methyl methanesulfonate, dependent on an active DNA damage checkpoint. Rad55p modification was also observed after gamma ray and UV radiation. The rapid time course of phosphorylation and the recombination defects identified in checkpoint-deficient cells are consistent with a role of the DNA damage checkpoint in activating recombinational repair. Rad55p phosphorylation possibly affects the balance between different competing DNA repair pathways.
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3

Stokes, Matthew P., Ruth Van Hatten, Howard D. Lindsay, and W. Matthew Michael. "DNA replication is required for the checkpoint response to damaged DNA in Xenopus egg extracts." Journal of Cell Biology 158, no. 5 (September 2, 2002): 863–72. http://dx.doi.org/10.1083/jcb.200204127.

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Alkylating agents, such as methyl methanesulfonate (MMS), damage DNA and activate the DNA damage checkpoint. Although many of the checkpoint proteins that transduce damage signals have been identified and characterized, the mechanism that senses the damage and activates the checkpoint is not yet understood. To address this issue for alkylation damage, we have reconstituted the checkpoint response to MMS in Xenopus egg extracts. Using four different indicators for checkpoint activation (delay on entrance into mitosis, slowing of DNA replication, phosphorylation of the Chk1 protein, and physical association of the Rad17 checkpoint protein with damaged DNA), we report that MMS-induced checkpoint activation is dependent upon entrance into S phase. Additionally, we show that the replication of damaged double-stranded DNA, and not replication of damaged single-stranded DNA, is the molecular event that activates the checkpoint. Therefore, these data provide direct evidence that replication forks are an obligate intermediate in the activation of the DNA damage checkpoint.
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4

Iyer, Divya Ramalingam, and Nicholas Rhind. "Checkpoint regulation of replication forks: global or local?" Biochemical Society Transactions 41, no. 6 (November 20, 2013): 1701–5. http://dx.doi.org/10.1042/bst20130197.

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Cell-cycle checkpoints are generally global in nature: one unattached kinetochore prevents the segregation of all chromosomes; stalled replication forks inhibit late origin firing throughout the genome. A potential exception to this rule is the regulation of replication fork progression by the S-phase DNA damage checkpoint. In this case, it is possible that the checkpoint is global, and it slows all replication forks in the genome. However, it is also possible that the checkpoint acts locally at sites of DNA damage, and only slows those forks that encounter DNA damage. Whether the checkpoint regulates forks globally or locally has important mechanistic implications for how replication forks deal with damaged DNA during S-phase.
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5

Audry, Julien, Jinyu Wang, Jessica R. Eisenstatt, Kathleen L. Berkner, and Kurt W. Runge. "The inhibition of checkpoint activation by telomeres does not involve exclusion of dimethylation of histone H4 lysine 20 (H4K20me2)." F1000Research 7 (October 9, 2018): 1027. http://dx.doi.org/10.12688/f1000research.15166.2.

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DNA double-strand breaks (DSBs) activate the DNA damage checkpoint machinery to pause or halt the cell cycle. Telomeres, the specific DNA-protein complexes at linear eukaryotic chromosome ends, are capped DSBs that do not activate DNA damage checkpoints. This “checkpoint privileged” status of telomeres was previously investigated in the yeast Schizosaccharomyces pombelacking the major double-stranded telomere DNA binding protein Taz1. Telomeric DNA repeats in cells lacking Taz1 are 10 times longer than normal and contain single-stranded DNA regions. DNA damage checkpoint proteins associate with these damaged telomeres, but the DNA damage checkpoint is not activated. This severing of the DNA damage checkpoint signaling pathway was reported to stem from exclusion of histone H4 lysine 20 dimethylation (H4K20me2) from telomeric nucleosomes in both wild type cells and cells lacking Taz1. However, experiments to identify the mechanism of this exclusion failed, prompting our re-evaluation of H4K20me2 levels at telomeric chromatin. In this short report, we used an extensive series of controls to identify an antibody specific for the H4K20me2 modification and show that the level of this modification is the same at telomeres and internal loci in both wild type cells and those lacking Taz1. Consequently, telomeres must block activation of the DNA Damage Response by another mechanism that remains to be determined.
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6

Garber, Peter M., and Jasper Rine. "Overlapping Roles of the Spindle Assembly and DNA Damage Checkpoints in the Cell-Cycle Response to Altered Chromosomes in Saccharomyces cerevisiae." Genetics 161, no. 2 (June 1, 2002): 521–34. http://dx.doi.org/10.1093/genetics/161.2.521.

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Abstract The MAD2-dependent spindle checkpoint blocks anaphase until all chromosomes have achieved successful bipolar attachment to the mitotic spindle. The DNA damage and DNA replication checkpoints block anaphase in response to DNA lesions that may include single-stranded DNA and stalled replication forks. Many of the same conditions that activate the DNA damage and DNA replication checkpoints also activated the spindle checkpoint. The mad2Δ mutation partially relieved the arrest responses of cells to mutations affecting the replication proteins Mcm3p and Pol1p. Thus a previously unrecognized aspect of spindle checkpoint function may be to protect cells from defects in DNA replication. Furthermore, in cells lacking either the DNA damage or the DNA replication checkpoints, the spindle checkpoint contributed to the arrest responses of cells to the DNA-damaging agent methyl methanesulfonate, the replication inhibitor hydroxyurea, and mutations affecting Mcm2p and Orc2p. Thus the spindle checkpoint was sensitive to a wider range of chromosomal perturbations than previously recognized. Finally, the DNA replication checkpoint did not contribute to the arrests of cells in response to mutations affecting ORC, Mcm proteins, or DNA polymerase δ. Thus the specificity of this checkpoint may be more limited than previously recognized.
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7

Rhind, Nicholas, and Paul Russell. "The Schizosaccharomyces pombe S-Phase Checkpoint Differentiates Between Different Types of DNA Damage." Genetics 149, no. 4 (August 1, 1998): 1729–37. http://dx.doi.org/10.1093/genetics/149.4.1729.

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Abstract We have identified an S-phase DNA damage checkpoint in Schizosaccharomyces pombe. This checkpoint is dependent on Rad3, the S. pombe homolog of the mammalian ATM/ATR checkpoint proteins, and Cds1. Cds1 had previously been believed to be involved only in the replication checkpoint. The requirement of Cds1 in the DNA damage checkpoint suggests that Cds1 may be a general target of S-phase checkpoints. Unlike other checkpoints, the S. pombe S-phase DNA damage checkpoint discriminates between different types of damage. UV-irradiation, which causes base modification that can be repaired during G1 and S-phase, invokes the checkpoint, while γ-irradiation, which causes double-stranded breaks that cannot be repaired by a haploid cell if induced before replication, does not invoke the checkpoint. Because the same genes are required to respond to UV- and γ-irradiation during G2, this discrimination may represent an active suppression of the γ response during S-phase.
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8

Paciotti, Vera, Michela Clerici, Maddalena Scotti, Giovanna Lucchini, and Maria Pia Longhese. "Characterization of mec1Kinase-Deficient Mutants and of New Hypomorphic mec1Alleles Impairing Subsets of the DNA Damage Response Pathway." Molecular and Cellular Biology 21, no. 12 (June 15, 2001): 3913–25. http://dx.doi.org/10.1128/mcb.21.12.3913-3925.2001.

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ABSTRACT DNA damage checkpoints lead to the inhibition of cell cycle progression following DNA damage. The Saccharomyces cerevisiae Mec1 checkpoint protein, a phosphatidylinositol kinase-related protein, is required for transient cell cycle arrest in response to DNA damage or DNA replication defects. We show thatmec1 kinase-deficient (mec1kd) mutants are indistinguishable from mec1Δ cells, indicating that the Mec1 conserved kinase domain is required for all known Mec1 functions, including cell viability and proper DNA damage response. Mec1kd variants maintain the ability to physically interact with both Ddc2 and wild-type Mec1 and cause dominant checkpoint defects when overproduced in MEC1 cells, impairing the ability of cells to slow down S phase entry and progression after DNA damage in G1 or during S phase. Conversely, an excess of Mec1kd inMEC1 cells does not abrogate the G2/M checkpoint, suggesting that Mec1 functions required for response to aberrant DNA structures during specific cell cycle stages can be separable. In agreement with this hypothesis, we describe two new hypomorphic mec1 mutants that are completely defective in the G1/S and intra-S DNA damage checkpoints but properly delay nuclear division after UV irradiation in G2. The finding that these mutants, although indistinguishable frommec1Δ cells with respect to the ability to replicate a damaged DNA template, do not lose viability after UV light and methyl methanesulfonate treatment suggests that checkpoint impairments do not necessarily result in hypersensitivity to DNA-damaging agents.
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9

Audry, Julien, Jinyu Wang, Jessica R. Eisenstatt, Kathleen L. Berkner, and Kurt W. Runge. "The inhibition of checkpoint activation by telomeres does not involve exclusion of dimethylation of histone H4 lysine 20 (H4K20me2)." F1000Research 7 (July 9, 2018): 1027. http://dx.doi.org/10.12688/f1000research.15166.1.

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DNA double-strand (DSBs) breaks activate the DNA damage checkpoint machinery to pause or halt the cell cycle. Telomeres, the specific DNA-protein complexes at linear eukaryotic chromosome ends, are capped DSBs that do not activate DNA damage checkpoints. This “checkpoint privileged” status of telomeres was previously investigated in the yeast Schizosaccharomyces pombe lacking the major double-stranded telomere DNA binding protein Taz1. Telomeric DNA repeats in cells lacking Taz1 are 10 times longer than normal and contain single-stranded DNA regions. DNA damage checkpoint proteins associate with these damaged telomeres, but the DNA damage checkpoint is not activated. This severing of the DNA damage checkpoint signaling pathway was reported to stem from exclusion of histone H4 lysine 20 dimethylation (H4K20me2) from telomeric nucleosomes in both wild type cells and cells lacking Taz1. However, experiments to identify the mechanism of this exclusion failed, prompting our re-evaluation of H4K20me2 levels at telomeric chromatin. In this short report, we used an extensive series of controls to identify an antibody specific for the H4K20me2 modification and show that the level of this modification is the same at telomeres and internal loci in both wild type cells and those lacking Taz1. Consequently, telomeres must block activation of the DNA Damage Response by another mechanism that remains to be determined.
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10

Toh, G. W. L., and N. F. Lowndes. "Role of the Saccharomyces cerevisiae Rad9 protein in sensing and responding to DNA damage." Biochemical Society Transactions 31, no. 1 (February 1, 2003): 242–46. http://dx.doi.org/10.1042/bst0310242.

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Eukaryotic cells have evolved surveillance mechanisms, known as DNA-damage checkpoints, that sense and respond to genome damage. DNA-damage checkpoint pathways ensure co-ordinated cellular responses to DNA damage, including cell cycle delays and activation of repair mechanisms. RAD9, from Saccharomyces cerevisiae, was the first damage checkpoint gene to be identified, although its biochemical function remained unknown until recently. This review examines briefly work that provides significant insight into how Rad9 activates the checkpoint signalling kinase Rad53.
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11

Chahwan, Charly, Toru M. Nakamura, Sasirekha Sivakumar, Paul Russell, and Nicholas Rhind. "The Fission Yeast Rad32 (Mre11)-Rad50-Nbs1 Complex Is Required for the S-Phase DNA Damage Checkpoint." Molecular and Cellular Biology 23, no. 18 (September 15, 2003): 6564–73. http://dx.doi.org/10.1128/mcb.23.18.6564-6573.2003.

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ABSTRACT Mre11, Rad50, and Nbs1 form a conserved heterotrimeric complex that is involved in recombination and DNA damage checkpoints. Mutations in this complex disrupt the S-phase DNA damage checkpoint, the checkpoint which slows replication in response to DNA damage, and cause chromosome instability and cancer in humans. However, how these proteins function and specifically where they act in the checkpoint signaling pathway remain crucial questions. We identified fission yeast Nbs1 by using a comparative genomic approach and showed that the genes for human Nbs1 and fission yeast Nbs1 and that for their budding yeast counterpart, Xrs2, are members of an evolutionarily related but rapidly diverging gene family. Fission yeast Nbs1, Rad32 (the homolog of Mre11), and Rad50 are involved in DNA damage repair, telomere regulation, and the S-phase DNA damage checkpoint. However, they are not required for G2 DNA damage checkpoint. Our results suggest that a complex of Rad32, Rad50, and Nbs1 acts specifically in the S-phase branch of the DNA damage checkpoint and is not involved in general DNA damage recognition or signaling.
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12

Zhou, Qing, Kieu T. M. Pham, Huiqing Hu, Yasuhiro Kurasawa, and Ziyin Li. "A kinetochore-based ATM/ATR-independent DNA damage checkpoint maintains genomic integrity in trypanosomes." Nucleic Acids Research 47, no. 15 (May 31, 2019): 7973–88. http://dx.doi.org/10.1093/nar/gkz476.

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Abstract DNA damage-induced cell cycle checkpoints serve as surveillance mechanisms to maintain genomic stability, and are regulated by ATM/ATR-mediated signaling pathways that are conserved from yeast to humans. Trypanosoma brucei, an early divergent microbial eukaryote, lacks key components of the conventional DNA damage-induced G2/M cell cycle checkpoint and the spindle assembly checkpoint, and nothing is known about how T. brucei controls its cell cycle checkpoints. Here we discover a kinetochore-based, DNA damage-induced metaphase checkpoint in T. brucei. MMS-induced DNA damage triggers a metaphase arrest by modulating the abundance of the outer kinetochore protein KKIP5 in an Aurora B kinase- and kinetochore-dependent, but ATM/ATR-independent manner. Overexpression of KKIP5 arrests cells at metaphase through stabilizing the mitotic cyclin CYC6 and the cohesin subunit SCC1, mimicking DNA damage-induced metaphase arrest, whereas depletion of KKIP5 alleviates the DNA damage-induced metaphase arrest and causes chromosome mis-segregation and aneuploidy. These findings suggest that trypanosomes employ a novel DNA damage-induced metaphase checkpoint to maintain genomic integrity.
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13

Pankratz, Daniel G., and Susan L. Forsburg. "Meiotic S-Phase Damage Activates Recombination without Checkpoint Arrest." Molecular Biology of the Cell 16, no. 4 (April 2005): 1651–60. http://dx.doi.org/10.1091/mbc.e04-10-0934.

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Checkpoints operate during meiosis to ensure the completion of DNA synthesis and programmed recombination before the initiation of meiotic divisions. Studies in the fission yeast Schizosaccharomyces pombe suggest that the meiotic response to DNA damage due to a failed replication checkpoint response differs substantially from the vegetative response, and may be influenced by the presence of homologous chromosomes. The checkpoint responses to DNA damage during fission yeast meiosis are not well characterized. Here we report that DNA damage induced during meiotic S-phase does not activate checkpoint arrest. We also find that in wild-type cells, markers for DNA breaks can persist at least to the first meiotic division. We also observe increased spontaneous S-phase damage in checkpoint mutants, which is repaired by recombination without activating checkpoint arrest. Our results suggest that fission yeast meiosis is exceptionally tolerant of DNA damage, and that some forms of spontaneous S-phase damage can be repaired by recombination without activating checkpoint arrest.
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14

Weinert, Ted. "DNA Damage and Checkpoint Pathways." Cell 94, no. 5 (September 1998): 555–58. http://dx.doi.org/10.1016/s0092-8674(00)81597-4.

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15

Muzi-Falconi, Marco, and John Petrini. "Checkpoint response to DNA damage." DNA Repair 8, no. 9 (September 2, 2009): 973. http://dx.doi.org/10.1016/j.dnarep.2009.07.005.

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16

Rhind, Nicholas, and Paul Russell. "Roles of the Mitotic Inhibitors Wee1 and Mik1 in the G2 DNA Damage and Replication Checkpoints." Molecular and Cellular Biology 21, no. 5 (March 1, 2001): 1499–508. http://dx.doi.org/10.1128/mcb.21.5.1499-1508.2001.

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ABSTRACT The G2 DNA damage and DNA replication checkpoints in many organisms act through the inhibitory phosphorylation of Cdc2 on tyrosine-15. This phosphorylation is catalyzed by the Wee1/Mik1 family of kinases. However, the in vivo role of these kinases in checkpoint regulation has been unclear. We show that, in the fission yeastSchizosaccharomyces pombe, Mik1 is a target of both checkpoints and that the regulation of Mik1 is, on its own, sufficient to delay mitosis in response to the checkpoints. Mik1 appears to have two roles in the DNA damage checkpoint; one in the establishment of the checkpoint and another in its maintenance. In contrast, Wee1 does not appear to be involved in the establishment of either checkpoint.
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17

Taricani, Lorena, and Teresa S. F. Wang. "Rad4TopBP1, a Scaffold Protein, Plays Separate Roles in DNA Damage and Replication Checkpoints and DNA Replication." Molecular Biology of the Cell 17, no. 8 (August 2006): 3456–68. http://dx.doi.org/10.1091/mbc.e06-01-0056.

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Rad4TopBP1, a BRCT domain protein, is required for both DNA replication and checkpoint responses. Little is known about how the multiple roles of Rad4TopBP1 are coordinated in maintaining genome integrity. We show here that Rad4TopBP1 of fission yeast physically interacts with the checkpoint sensor proteins, the replicative DNA polymerases, and a WD-repeat protein, Crb3. We identified four novel mutants to investigate how Rad4TopBP1 could have multiple roles in maintaining genomic integrity. A novel mutation in the third BRCT domain of rad4+TopBP1 abolishes DNA damage checkpoint response, but not DNA replication, replication checkpoint, and cell cycle progression. This mutant protein is able to associate with all three replicative polymerases and checkpoint proteins Rad3ATR-Rad26ATRIP, Hus1, Rad9, and Rad17 but has a compromised association with Crb3. Furthermore, the damaged-induced Rad9 phosphorylation is significantly reduced in this rad4TopBP1 mutant. Genetic and biochemical analyses suggest that Crb3 has a role in the maintenance of DNA damage checkpoint and influences the Rad4TopBP1 damage checkpoint function. Taken together, our data suggest that Rad4TopBP1 provides a scaffold to a large complex containing checkpoint and replication proteins thereby separately enforcing checkpoint responses to DNA damage and replication perturbations during the cell cycle.
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18

MURAKAMI, Hiroshi, and Paul NURSE. "DNA replication and damage checkpoints and meiotic cell cycle controls in the fission and budding yeasts." Biochemical Journal 349, no. 1 (June 26, 2000): 1–12. http://dx.doi.org/10.1042/bj3490001.

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The cell cycle checkpoint mechanisms ensure the order of cell cycle events to preserve genomic integrity. Among these, the DNA-replication and DNA-damage checkpoints prevent chromosome segregation when DNA replication is inhibited or DNA is damaged. Recent studies have identified an outline of the regulatory networks for both of these controls, which apparently operate in all eukaryotes. In addition, it appears that these checkpoints have two arrest points, one is just before entry into mitosis and the other is prior to chromosome separation. The former point requires the central cell-cycle regulator Cdc2 kinase, whereas the latter involves several key regulators and substrates of the ubiquitin ligase called the anaphase promoting complex. Linkages between these cell-cycle regulators and several key checkpoint proteins are beginning to emerge. Recent findings on post-translational modifications and protein-protein interactions of the checkpoint proteins provide new insights into the checkpoint responses, although the functional significance of these biochemical properties often remains unclear. We have reviewed the molecular mechanisms acting at the DNA-replication and DNA-damage checkpoints in the fission yeast Schizosaccharomyces pombe, and the modifications of these controls during the meiotic cell cycle. We have made comparisons with the controls in fission yeast and other organisms, mainly the distantly related budding yeast.
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19

Klein, Hannah L. "Spontaneous Chromosome Loss in Saccharomyces cerevisiae Is Suppressed by DNA Damage Checkpoint Functions." Genetics 159, no. 4 (December 1, 2001): 1501–9. http://dx.doi.org/10.1093/genetics/159.4.1501.

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Abstract Genomic instability is one of the hallmarks of cancer cells and is often the causative factor in revealing recessive gene mutations that progress cells along the pathway to unregulated growth. Genomic instability can take many forms, including aneuploidy and changes in chromosome structure. Chromosome loss, loss and reduplication, and deletions are the majority events that result in loss of heterozygosity (LOH). Defective DNA replication, repair, and recombination can significantly increase the frequency of spontaneous genomic instability. Recently, DNA damage checkpoint functions that operate during the S-phase checkpoint have been shown to suppress spontaneous chromosome rearrangements in haploid yeast strains. To further study the role of DNA damage checkpoint functions in genomic stability, we have determined chromosome loss in DNA damage checkpoint-deficient yeast strains. We have found that the DNA damage checkpoints are essential for preserving the normal chromosome number and act synergistically with homologous recombination functions to ensure that chromosomes are segregated correctly to daughter cells. Failure of either of these processes increases LOH events. However, loss of the G2/M checkpoint does not result in an increase in chromosome loss, suggesting that it is the various S-phase DNA damage checkpoints that suppress chromosome loss. The mec1 checkpoint function mutant, defective in the yeast ATR homolog, results in increased recombination through a process that is distinct from that operative in wild-type cells.
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20

Kousholt, Arne Nedergaard, Kasper Fugger, Saskia Hoffmann, Brian D. Larsen, Tobias Menzel, Alessandro A. Sartori, and Claus Storgaard Sørensen. "CtIP-dependent DNA resection is required for DNA damage checkpoint maintenance but not initiation." Journal of Cell Biology 197, no. 7 (June 25, 2012): 869–76. http://dx.doi.org/10.1083/jcb.201111065.

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To prevent accumulation of mutations, cells respond to DNA lesions by blocking cell cycle progression and initiating DNA repair. Homology-directed repair of DNA breaks requires CtIP-dependent resection of the DNA ends, which is thought to play a key role in activation of ATR (ataxia telangiectasia mutated and Rad3 related) and CHK1 kinases to induce the cell cycle checkpoint. In this paper, we show that CHK1 was rapidly and robustly activated before detectable end resection. Moreover, we show that the key resection factor CtIP was dispensable for initial ATR–CHK1 activation after DNA damage by camptothecin and ionizing radiation. In contrast, we find that DNA end resection was critically required for sustained ATR–CHK1 checkpoint signaling and for maintaining both the intra–S- and G2-phase checkpoints. Consequently, resection-deficient cells entered mitosis with persistent DNA damage. In conclusion, we have uncovered a temporal program of checkpoint activation, where CtIP-dependent DNA end resection is required for sustained checkpoint signaling.
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21

Baber-Furnari, Beth A., Nick Rhind, Michael N. Boddy, Paul Shanahan, Antonia Lopez-Girona, and Paul Russell. "Regulation of Mitotic Inhibitor Mik1 Helps to Enforce the DNA Damage Checkpoint." Molecular Biology of the Cell 11, no. 1 (January 2000): 1–11. http://dx.doi.org/10.1091/mbc.11.1.1.

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The protein kinase Chk1 enforces the DNA damage checkpoint. This checkpoint delays mitosis until damaged DNA is repaired. Chk1 regulates the activity and localization of Cdc25, the tyrosine phosphatase that activates the cdk Cdc2. Here we report that Mik1, a tyrosine kinase that inhibits Cdc2, is positively regulated by the DNA damage checkpoint. Mik1 is required for checkpoint response in strains that lack Cdc25. Long-term DNA damage checkpoint arrest fails inΔmik1 cells. DNA damage increases Mik1 abundance in a Chk1-dependent manner. Ubiquitinated Mik1 accumulates in a proteasome mutant, which indicates that Mik1 normally has a short half-life. Thus, the DNA damage checkpoint might regulate Mik1 degradation. Mik1 protein and mRNA oscillate during the unperturbed cell cycle, with peak amounts detected around S phase. These data indicate that regulation of Mik1 abundance helps to couple mitotic onset to the completion of DNA replication and repair. Coordinated negative regulation of Cdc25 and positive regulation of Mik1 ensure the effective operation of the DNA damage checkpoint.
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22

Humpal, Stephen E., David A. Robinson, and Jocelyn E. Krebs. "Marks to stop the clock: histone modifications and checkpoint regulation in the DNA damage responseThis paper is one of a selection of papers published in this Special Issue, entitled 29th Annual International Asilomar Chromatin and Chromosomes Conference, and has undergone the Journal’s usual peer review process." Biochemistry and Cell Biology 87, no. 1 (February 2009): 243–53. http://dx.doi.org/10.1139/o08-109.

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DNA damage from endogenous and exogenous sources occurs throughout the cell cycle. In response to this damage, cells have developed a series of biochemical responses that allow them to recover from DNA damage and prevent mutations from being passed on to daughter cells. An important part of the DNA damage response is the ability to halt the progression of the cell cycle, allowing damaged DNA to be repaired. The cell cycle can be halted at semi-discrete times, called checkpoints, which occur at critical stages during the cell cycle. Recent work in our laboratory and by others has shown the importance of post-translational histone modifications in the DNA damage response. While many histone modifications have been identified that appear to facilitate repair per se, there have been surprisingly few links between these modifications and DNA damage checkpoints. Here, we review how modifications to histone H2A serine 129 (HSA129) and histone H3 lysine 79 (H3K79) contribute to the stimulation of the G1/S checkpoint. We also discuss recent findings that conflict with the current model of the way methylated H3K79 interacts with the checkpoint adaptor protein Rad9.
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23

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 (March 1, 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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24

Peng, Aimin, Andrea L. Lewellyn, and James L. Maller. "Undamaged DNA Transmits and Enhances DNA Damage Checkpoint Signals in Early Embryos." Molecular and Cellular Biology 27, no. 19 (July 30, 2007): 6852–62. http://dx.doi.org/10.1128/mcb.00195-07.

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ABSTRACT In Xenopus laevis embryos, the midblastula transition (MBT) at the 12th cell division marks initiation of critical developmental events, including zygotic transcription and the abrupt inclusion of gap phases into the cell cycle. Interestingly, although an ionizing radiation-induced checkpoint response is absent in pre-MBT embryos, introduction of a threshold amount of undamaged plasmid or sperm DNA allows a DNA damage checkpoint response to be activated. We show here that undamaged threshold DNA directly participates in checkpoint signaling, as judged by several dynamic changes, including H2AX phosphorylation, ATM phosphorylation and loading onto chromatin, and Chk1/Chk2 phosphorylation and release from nuclear DNA. These responses on physically separate threshold DNA require γ-H2AX and are triggered by an ATM-dependent soluble signal initiated by damaged DNA. The signal persists in egg extracts even after damaged DNA is removed from the system, indicating that the absence of damaged DNA is not sufficient to end the checkpoint response. The results identify a novel mechanism by which undamaged DNA enhances checkpoint signaling and provide an example of how the transition to cell cycle checkpoint activation during development is accomplished by maternally programmed increases in the DNA-to-cytoplasm ratio.
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25

LIU, Wei-Feng, Shan-Shan YU, Guan-Jun CHEN, and Yue-Zhong LI. "DNA Damage Checkpoint, Damage Repair, and Genome Stability." Acta Genetica Sinica 33, no. 5 (May 2006): 381–90. http://dx.doi.org/10.1016/s0379-4172(06)60064-4.

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26

Verma, Nagendra, Matteo Franchitto, Azzurra Zonfrilli, Samantha Cialfi, Rocco Palermo, and Claudio Talora. "DNA Damage Stress: Cui Prodest?" International Journal of Molecular Sciences 20, no. 5 (March 1, 2019): 1073. http://dx.doi.org/10.3390/ijms20051073.

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DNA is an entity shielded by mechanisms that maintain genomic stability and are essential for living cells; however, DNA is constantly subject to assaults from the environment throughout the cellular life span, making the genome susceptible to mutation and irreparable damage. Cells are prepared to mend such events through cell death as an extrema ratio to solve those threats from a multicellular perspective. However, in cells under various stress conditions, checkpoint mechanisms are activated to allow cells to have enough time to repair the damaged DNA. In yeast, entry into the cell cycle when damage is not completely repaired represents an adaptive mechanism to cope with stressful conditions. In multicellular organisms, entry into cell cycle with damaged DNA is strictly forbidden. However, in cancer development, individual cells undergo checkpoint adaptation, in which most cells die, but some survive acquiring advantageous mutations and selfishly evolve a conflictual behavior. In this review, we focus on how, in cancer development, cells rely on checkpoint adaptation to escape DNA stress and ultimately to cell death.
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27

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 (August 15, 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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28

Schollaert, Kaila L., Julie M. Poisson, Jennifer S. Searle, Jennifer A. Schwanekamp, Craig R. Tomlinson, and Yolanda Sanchez. "A Role for Saccharomyces cerevisiae Chk1p in the Response to Replication Blocks." Molecular Biology of the Cell 15, no. 9 (September 2004): 4051–63. http://dx.doi.org/10.1091/mbc.e03-11-0792.

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Replication blocks and DNA damage incurred during S phase activate the S-phase and intra-S-phase checkpoint responses, respectively, regulated by the Atrp and Chk1p checkpoint kinases in metazoans. In Saccharomyces cerevisiae, these checkpoints are regulated by the Atrp homologue Mec1p and the kinase Rad53p. A conserved role of these checkpoints is to block mitotic progression until DNA replication and repair are completed. In S. cerevisiae, these checkpoints include a transcriptional response regulated by the kinase Dun1p; however, dun1Δ cells are proficient for the S-phase-checkpoint-induced anaphase block. Yeast Chk1p kinase regulates the metaphase-to-anaphase transition in the DNA-damage checkpoint pathway via securin (Pds1p) phosphorylation. However, like Dun1p, yeast Chk1p is not required for the S-phase-checkpoint-induced anaphase block. Here we report that Chk1p has a role in the intra-S-phase checkpoint activated when yeast cells replicate their DNA in the presence of low concentrations of hydroxyurea (HU). Chk1p was modified and Pds1p was transiently phosphorylated in this response. Cells lacking Dun1p were dependent on Chk1p for survival in HU, and chk1Δ dun1Δ cells were defective in the recovery from replication interference caused by transient HU exposure. These studies establish a relationship between the S-phase and DNA-damage checkpoint pathways in S. cerevisiae and suggest that at least in some genetic backgrounds, the Chk1p/securin pathway is required for the recovery from stalled or collapsed replication forks.
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29

Collins, Josie K., and Keith T. Jones. "DNA damage responses in mammalian oocytes." Reproduction 152, no. 1 (July 2016): R15—R22. http://dx.doi.org/10.1530/rep-16-0069.

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DNA damage acquired during meiosis can lead to infertility and miscarriage. Hence, it should be important for an oocyte to be able to detect and respond to such events in order to make a healthy egg. Here, the strategies taken by oocytes during their stages of growth to respond to DNA damaging events are reviewed. In particular, recent evidence of a novel pathway in fully grown oocytes helps prevent the formation of mature eggs with DNA damage. It has been found that fully grown germinal vesicle stage oocytes that have been DNA damaged do not arrest at this point in meiosis, but instead undergo meiotic resumption and stall during the first meiotic division. The Spindle Assembly Checkpoint, which is a well-known mitotic pathway employed by somatic cells to monitor chromosome attachment to spindle microtubules, appears to be utilised by oocytes also to respond to DNA damage. As such maturing oocytes are arrested at metaphase I due to an active Spindle Assembly Checkpoint. This is surprising given this checkpoint has been previously studied in oocytes and considered to be weak and ineffectual because of its poor ability to be activated in response to microtubule attachment errors. Therefore, the involvement of the Spindle Assembly Checkpoint in DNA damage responses of mature oocytes during meiosis I uncovers a novel second function for this ubiquitous cellular checkpoint.
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30

Chow, Jeremy P. H., Wai Yi Siu, Tsz Kan Fung, Wan Mui Chan, Anita Lau, Talha Arooz, Chuen-Pei Ng, Katsumi Yamashita, and Randy Y. C. Poon. "DNA Damage during the Spindle-Assembly Checkpoint Degrades CDC25A, Inhibits Cyclin–CDC2 Complexes, and Reverses Cells to Interphase." Molecular Biology of the Cell 14, no. 10 (October 2003): 3989–4002. http://dx.doi.org/10.1091/mbc.e03-03-0168.

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Cell cycle checkpoints that monitor DNA damage and spindle assembly are essential for the maintenance of genetic integrity, and drugs that target these checkpoints are important chemotherapeutic agents. We have examined how cells respond to DNA damage while the spindle-assembly checkpoint is activated. Single cell electrophoresis and phosphorylation of histone H2AX indicated that several chemotherapeutic agents could induce DNA damage during mitotic block. DNA damage during mitotic block triggered CDC2 inactivation, histone H3 dephosphorylation, and chromosome decondensation. Cells did not progress into G1 but seemed to retract to a G2-like state containing 4N DNA content, with stabilized cyclin A and cyclin B1 binding to Thr14/Tyr15-phosphorylated CDC2. The loss of mitotic cells was not due to cell death because there was no discernible effect on caspase-3 activation, DNA fragmentation, or viability. Extensive DNA damage during mitotic block inactivated cyclin B1-CDC2 and prevented G1 entry when the block was removed. The mitotic DNA damage responses were independent of p53 and pRb, but they were dependent on ATM. CDC25A that accumulated during mitosis was rapidly destroyed after DNA damage in an ATM-dependent manner. Ectopic expression of CDC25A or nonphosphorylatable CDC2 effectively inhibited the dephosphorylation of histone H3 after DNA damage. Hence, although spindle disruption and DNA damage provide conflicting signals to regulate CDC2, the negative regulation by the DNA damage checkpoint could overcome the positive regulation by the spindle-assembly checkpoint.
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31

Berens, Theresa J., and David P. Toczyski. "Colocalization of Mec1 and Mrc1 is sufficient for Rad53 phosphorylation in vivo." Molecular Biology of the Cell 23, no. 6 (March 15, 2012): 1058–67. http://dx.doi.org/10.1091/mbc.e11-10-0852.

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When DNA is damaged or DNA replication goes awry, cells activate checkpoints to allow time for damage to be repaired and replication to complete. In Saccharomyces cerevisiae, the DNA damage checkpoint, which responds to lesions such as double-strand breaks, is activated when the lesion promotes the association of the sensor kinase Mec1 and its targeting subunit Ddc2 with its activators Ddc1 (a member of the 9-1-1 complex) and Dpb11. It has been more difficult to determine what role these Mec1 activators play in the replication checkpoint, which recognizes stalled replication forks, since Dpb11 has a separate role in DNA replication itself. Therefore we constructed an in vivo replication-checkpoint mimic that recapitulates Mec1-dependent phosphorylation of the effector kinase Rad53, a crucial step in checkpoint activation. In the endogenous replication checkpoint, Mec1 phosphorylation of Rad53 requires Mrc1, a replisome component. The replication-checkpoint mimic requires colocalization of Mrc1-LacI and Ddc2-LacI and is independent of both Ddc1 and Dpb11. We show that these activators are also dispensable for Mec1 activity and cell survival in the endogenous replication checkpoint but that Ddc1 is absolutely required in the absence of Mrc1. We propose that colocalization of Mrc1 and Mec1 is the minimal signal required to activate the replication checkpoint.
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32

Ivanova, Tsvetomira, Isabel Alves-Rodrigues, Blanca Gómez-Escoda, Chaitali Dutta, James A. DeCaprio, Nick Rhind, Elena Hidalgo, and José Ayté. "The DNA damage and the DNA replication checkpoints converge at the MBF transcription factor." Molecular Biology of the Cell 24, no. 21 (November 2013): 3350–57. http://dx.doi.org/10.1091/mbc.e13-05-0257.

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In fission yeast cells, Cds1 is the effector kinase of the DNA replication checkpoint. We previously showed that when the DNA replication checkpoint is activated, the repressor Yox1 is phosphorylated and inactivated by Cds1, resulting in activation of MluI-binding factor (MBF)–dependent transcription. This is essential to reinitiate DNA synthesis and for correct G1-to-S transition. Here we show that Cdc10, which is an essential part of the MBF core, is the target of the DNA damage checkpoint. When fission yeast cells are treated with DNA-damaging agents, Chk1 is activated and phosphorylates Cdc10 at its carboxy-terminal domain. This modification is responsible for the repression of MBF-dependent transcription through induced release of MBF from chromatin. This inactivation of MBF is important for survival of cells challenged with DNA-damaging agents. Thus Yox1 and Cdc10 couple normal cell cycle regulation in unperturbed conditions and the DNA replication and DNA damage checkpoints into a single transcriptional complex.
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33

Rhind, N., and P. Russell. "Chk1 and Cds1: linchpins of the DNA damage and replication checkpoint pathways." Journal of Cell Science 113, no. 22 (November 15, 2000): 3889–96. http://dx.doi.org/10.1242/jcs.113.22.3889.

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Recent work on the mechanisms of DNA damage and replication cell cycle checkpoints has revealed great similarity between the checkpoint pathways of organisms as diverse as yeasts, flies and humans. However, there are differences in the ways these organisms regulate their cell cycles. To connect the conserved checkpoint pathways with various cell cycle targets requires an adaptable link that can target different cell cycle components in different organisms. The Chk1 and Cds1 protein kinases, downstream effectors in the checkpoint pathways, seem to play just such roles. Perhaps more surprisingly, the two kinases not only have different targets in different organisms but also seem to respond to different signals in different organisms. So, whereas in fission yeast Chk1 is required for the DNA damage checkpoint and Cds1 is specifically involved in the replication checkpoint, their roles seem to be shuffled in metazoans.
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34

Lim, Chiaw-Hwee, Shang-Wei Chong, and Yun-Jin Jiang. "Udu Deficiency Activates DNA Damage Checkpoint." Molecular Biology of the Cell 20, no. 19 (October 2009): 4183–93. http://dx.doi.org/10.1091/mbc.e09-02-0109.

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Udu has been shown to play an essential role during blood cell development; however, its roles in other cellular processes remain largely unexplored. In addition, ugly duckling (udu) mutants exhibited somite and myotome boundary defects. Our fluorescence-activated cell sorting analysis also showed that the loss of udu function resulted in defective cell cycle progression and comet assay indicated the presence of increased DNA damage in udutu24 mutants. We further showed that the extensive p53-dependent apoptosis in udutu24 mutants is a consequence of activation in the Atm–Chk2 pathway. Udu seems not to be required for DNA repair, because both wild-type and udu embryos similarly respond to and recover from UV treatment. Yeast two-hybrid and coimmunoprecipitation data demonstrated that PAH-L repeats and SANT-L domain of Udu interacts with MCM3 and MCM4. Furthermore, Udu is colocalized with 5-bromo-2′-deoxyuridine and heterochromatin during DNA replication, suggesting a role in maintaining genome integrity.
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35

O’Connell, Matthew J., Nancy C. Walworth, and Antony M. Carr. "The G2-phase DNA-damage checkpoint." Trends in Cell Biology 10, no. 7 (July 2000): 296–303. http://dx.doi.org/10.1016/s0962-8924(00)01773-6.

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36

Lisby, Michael, and Rodney Rothstein. "DNA damage checkpoint and repair centers." Current Opinion in Cell Biology 16, no. 3 (June 2004): 328–34. http://dx.doi.org/10.1016/j.ceb.2004.03.011.

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37

Longhese, M. P. "DNA damage checkpoint in budding yeast." EMBO Journal 17, no. 19 (October 1, 1998): 5525–28. http://dx.doi.org/10.1093/emboj/17.19.5525.

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38

Clémenson, Céline, and Marie-Claude Marsolier-Kergoat. "The Spindle Assembly Checkpoint Regulates the Phosphorylation State of a Subset of DNA Checkpoint Proteins in Saccharomyces cerevisiae." Molecular and Cellular Biology 26, no. 24 (October 23, 2006): 9149–61. http://dx.doi.org/10.1128/mcb.00310-06.

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ABSTRACT The DNA and the spindle assembly checkpoints play key roles in maintaining genomic integrity by coordinating cell responses to DNA lesions and spindle dysfunctions, respectively. These two surveillance pathways seem to operate mostly independently of one another, and little is known about their potential physiological connections. Here, we show that in Saccharomyces cerevisiae, the activation of the spindle assembly checkpoint triggers phosphorylation changes in two components of the DNA checkpoint, Rad53 and Rad9. These modifications are independent of the other DNA checkpoint proteins and are abolished in spindle checkpoint-defective mutants, hinting at specific functions for Rad53 and Rad9 in the spindle damage response. Moreover, we found that after UV irradiation, Rad9 phosphorylation is altered and Rad53 inactivation is accelerated when the spindle checkpoint is activated, which suggests the implication of the spindle checkpoint in the regulation of the DNA damage response.
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39

Mankouri, Hocine W., and Ian D. Hickson. "Top3 Processes Recombination Intermediates and Modulates Checkpoint Activity after DNA Damage." Molecular Biology of the Cell 17, no. 10 (October 2006): 4473–83. http://dx.doi.org/10.1091/mbc.e06-06-0516.

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Mutation of TOP3 in Saccharomyces cerevisiae causes poor growth, hyperrecombination, and a failure to fully activate DNA damage checkpoints in S phase. Here, we report that overexpression of a dominant-negative allele of TOP3, TOP3Y356F, which lacks the catalytic (decatenation) activity of Top3, causes impaired S-phase progression and the persistence of abnormal DNA structures (X-shaped DNA molecules) after exposure to methylmethanesulfonate. The impaired S-phase progression is due to a persistent checkpoint-mediated cell cycle delay and can be overridden by addition of caffeine. Hence, the catalytic activity of Top3 is not required for DNA damage checkpoint activation, but it is required for normal S-phase progression after DNA damage. We also present evidence that the checkpoint-mediated cell cycle delay and persistence of X-shaped DNA molecules resulting from overexpression of TOP3Y356F are downstream of Rad51 function. We propose that Top3 functions in S phase to both process homologous recombination intermediates and modulate checkpoint activity.
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40

Tavormina, P. A., Y. Wang, and D. J. Burke. "Differential requirements for DNA replication in the activation of mitotic checkpoints in Saccharomyces cerevisiae." Molecular and Cellular Biology 17, no. 6 (June 1997): 3315–22. http://dx.doi.org/10.1128/mcb.17.6.3315.

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Checkpoints prevent inaccurate chromosome segregation by inhibiting cell division when errors in mitotic processes are encountered. We used a temperature-sensitive mutation, dbf4, to examine the requirement for DNA replication in establishing mitotic checkpoint arrest. We used gamma-irradiation to induce DNA damage and hydroxyurea to limit deoxyribonucleotides in cells deprived of DBF4 function to investigate the requirement for DNA replication in DNA-responsive checkpoints. In the absence of DNA replication, mitosis was not inhibited by these treatments, which normally activate the DNA damage and DNA replication checkpoints. Our results support a model that indicates that the assembly of replication structures is critical for cells to respond to defects in DNA metabolism. We show that activating the spindle checkpoint with nocodazole does not require prior progression through S phase but does require a stable kinetochore.
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41

Collura, Ada, Joel Blaisonneau, Giuseppe Baldacci, and Stefania Francesconi. "The Fission Yeast Crb2/Chk1 Pathway Coordinates the DNA Damage and Spindle Checkpoint in Response to Replication Stress Induced by Topoisomerase I Inhibitor." Molecular and Cellular Biology 25, no. 17 (September 1, 2005): 7889–99. http://dx.doi.org/10.1128/mcb.25.17.7889-7899.2005.

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ABSTRACT Living organisms experience constant threats that challenge their genome stability. The DNA damage checkpoint pathway coordinates cell cycle progression with DNA repair when DNA is damaged, thus ensuring faithful transmission of the genome. The spindle assembly checkpoint inhibits chromosome segregation until all chromosomes are properly attached to the spindle, ensuring accurate partition of the genetic material. Both the DNA damage and spindle checkpoint pathways participate in genome integrity. However, no clear connection between these two pathways has been described. Here, we analyze mutants in the BRCT domains of fission yeast Crb2, which mediates Chk1 activation, and provide evidence for a novel function of the Chk1 pathway. When the Crb2 mutants experience damaged replication forks upon inhibition of the religation activity of topoisomerase I, the Chk1 DNA damage pathway induces sustained activation of the spindle checkpoint, which in turn delays metaphase-to-anaphase transition in a Mad2-dependent fashion. This new pathway enhances cell survival and genome stability when cells undergo replicative stress in the absence of a proficient G2/M DNA damage checkpoint.
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42

Kim, Hee-Sook, and Steven J. Brill. "Rfc4 Interacts with Rpa1 and Is Required for Both DNA Replication and DNA Damage Checkpoints in Saccharomyces cerevisiae." Molecular and Cellular Biology 21, no. 11 (June 1, 2001): 3725–37. http://dx.doi.org/10.1128/mcb.21.11.3725-3737.2001.

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ABSTRACT The large subunit of replication protein A (Rpa1) consists of three single-stranded DNA binding domains and an N-terminal domain (Rpa1N) of unknown function. To determine the essential role of this domain we searched for mutations that require wild-type Rpa1N for viability in yeast. A mutation in RFC4, encoding a small subunit of replication factor C (RFC), was found to display allele-specific interactions with mutations in the gene encoding Rpa1 (RFA1). Mutations that map to Rpa1N and confer sensitivity to the DNA synthesis inhibitor hydroxyurea, such asrfa1-t11, are lethal in combination withrfc4-2. The rfc4-2 mutant itself is sensitive to hydroxyurea, and like rfc2 and rfc5 strains, it exhibits defects in the DNA replication block and intra-S checkpoints. RFC4 and the DNA damage checkpoint geneRAD24 were found to be epistatic with respect to DNA damage sensitivity. We show that the rfc4-2 mutant is defective in the G1/S DNA damage checkpoint response and that both therfc4-2 and rfa1-t11 strains are defective in the G2/M DNA damage checkpoint. Thus, in addition to its essential role as part of the clamp loader in DNA replication, Rfc4 plays a role as a sensor in multiple DNA checkpoint pathways. Our results suggest that a physical interaction between Rfc4 and Rpa1N is required for both roles.
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43

Shimomura, Toshiyasu, Seiko Ando, Kunihiro Matsumoto, and Katsunori Sugimoto. "Functional and Physical Interaction between Rad24 and Rfc5 in the Yeast Checkpoint Pathways." Molecular and Cellular Biology 18, no. 9 (September 1, 1998): 5485–91. http://dx.doi.org/10.1128/mcb.18.9.5485.

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ABSTRACT The RFC5 gene encodes a small subunit of replication factor C (RFC) complex in Saccharomyces cerevisiae and has been shown to be required for the checkpoints which respond to replication block and DNA damage. Here we describe the isolation ofRAD24, known to play a role in the DNA damage checkpoint, as a dosage-dependent suppressor of rfc5-1. RAD24overexpression suppresses the sensitivity of rfc5-1 cells to DNA-damaging agents and the defect in DNA damage-induced Rad53 phosphorylation. Rad24, like Rfc5, is required for the regulation of Rad53 phosphorylation in response to DNA damage. The Rad24 protein, which is structurally related to the RFC subunits, interacts physically with RFC subunits Rfc2 and Rfc5 and cosediments with Rfc5. Although therad24Δ mutation alone does not cause a defect in the replication block checkpoint, it does enhance the defect inrfc5-1 mutants. Furthermore, overexpression ofRAD24 suppresses the rfc5-1 defect in the replication block checkpoint. Taken together, our results demonstrate a physical and functional interaction between Rad24 and Rfc5 in the checkpoint pathways.
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44

Yamada, Ayumi, Brad Duffy, Jennifer A. Perry, and Sally Kornbluth. "DNA replication checkpoint control of Wee1 stability by vertebrate Hsl7." Journal of Cell Biology 167, no. 5 (December 6, 2004): 841–49. http://dx.doi.org/10.1083/jcb.200406048.

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G2/M checkpoints prevent mitotic entry upon DNA damage or replication inhibition by targeting the Cdc2 regulators Cdc25 and Wee1. Although Wee1 protein stability is regulated by DNA-responsive checkpoints, the vertebrate pathways controlling Wee1 degradation have not been elucidated. In budding yeast, stability of the Wee1 homologue, Swe1, is controlled by a regulatory module consisting of the proteins Hsl1 and Hsl7 (histone synthetic lethal 1 and 7), which are targeted by the morphogenesis checkpoint to prevent Swe1 degradation when budding is inhibited. We report here the identification of Xenopus Hsl7 as a positive regulator of mitosis that is controlled, instead, by an entirely distinct checkpoint, the DNA replication checkpoint. Although inhibiting Hsl7 delayed mitosis, Hsl7 overexpression overrode the replication checkpoint, accelerating Wee1 destruction. Replication checkpoint activation disrupted Hsl7–Wee1 interactions, but binding was restored by active polo-like kinase. These data establish Hsl7 as a component of the replication checkpoint and reveal that similar cell cycle control modules can be co-opted for use by distinct checkpoints in different organsims.
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45

Moser, Bettina A., Jean-Marc Brondello, Beth Baber-Furnari, and Paul Russell. "Mechanism of Caffeine-Induced Checkpoint Override in Fission Yeast." Molecular and Cellular Biology 20, no. 12 (June 15, 2000): 4288–94. http://dx.doi.org/10.1128/mcb.20.12.4288-4294.2000.

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ABSTRACT Mitotic checkpoints restrain the onset of mitosis (M) when DNA is incompletely replicated or damaged. These checkpoints are conserved between the fission yeast Schizosaccharomyces pombe and mammals. In both types of organisms, the methylxanthine caffeine overrides the synthesis (S)-M checkpoint that couples mitosis to completion of DNA S phase. The molecular target of caffeine was sought in fission yeast. Caffeine prevented activation of Cds1 and phosphorylation of Chk1, two protein kinases that enforce the S-M checkpoint triggered by hydroxyurea. Caffeine did not inhibit these kinases in vitro but did inhibit Rad3, a kinase that regulates Cds1 and Chk1. In accordance with this finding, caffeine also overrode the G2-M DNA damage checkpoint that requires Rad3 function. Rad3 coprecipitated with Cds1 expressed at endogenous amounts, a finding that supports the hypothesis that Rad3 is involved in direct activation of Cds1.
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46

Lou, Zhenkun, Claudia Christiano Silva Chini, Katherine Minter-Dykhouse, and Junjie Chen. "Mediator of DNA Damage Checkpoint Protein 1 Regulates BRCA1 Localization and Phosphorylation in DNA Damage Checkpoint Control." Journal of Biological Chemistry 278, no. 16 (February 27, 2003): 13599–602. http://dx.doi.org/10.1074/jbc.c300060200.

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47

Kemp, Michael G., Laura A. Lindsey-Boltz, and Aziz Sancar. "The DNA Damage Response Kinases DNA-dependent Protein Kinase (DNA-PK) and Ataxia Telangiectasia Mutated (ATM) Are Stimulated by Bulky Adduct-containing DNA." Journal of Biological Chemistry 286, no. 22 (April 12, 2011): 19237–46. http://dx.doi.org/10.1074/jbc.m111.235036.

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A variety of environmental, carcinogenic, and chemotherapeutic agents form bulky lesions on DNA that activate DNA damage checkpoint signaling pathways in human cells. To identify the mechanisms by which bulky DNA adducts induce damage signaling, we developed an in vitro assay using mammalian cell nuclear extract and plasmid DNA containing bulky adducts formed by N-acetoxy-2-acetylaminofluorene or benzo(a)pyrene diol epoxide. Using this cell-free system together with a variety of pharmacological, genetic, and biochemical approaches, we identified the DNA damage response kinases DNA-dependent protein kinase (DNA-PK) and ataxia telangiectasia mutated (ATM) as bulky DNA damage-stimulated kinases that phosphorylate physiologically important residues on the checkpoint proteins p53, Chk1, and RPA. Consistent with these results, purified DNA-PK and ATM were directly stimulated by bulky adduct-containing DNA and preferentially associated with damaged DNA in vitro. Because the DNA damage response kinase ATM and Rad3-related (ATR) is also stimulated by bulky DNA adducts, we conclude that a common biochemical mechanism exists for activation of DNA-PK, ATM, and ATR by bulky adduct-containing DNA.
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48

Goff, Peter H., Rashmi Bhakuni, Thomas Pulliam, Jung Hyun Lee, Evan T. Hall, and Paul Nghiem. "Intersection of Two Checkpoints: Could Inhibiting the DNA Damage Response Checkpoint Rescue Immune Checkpoint-Refractory Cancer?" Cancers 13, no. 14 (July 8, 2021): 3415. http://dx.doi.org/10.3390/cancers13143415.

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Metastatic cancers resistant to immunotherapy require novel management strategies. DNA damage response (DDR) proteins, including ATR (ataxia telangiectasia and Rad3-related), ATM (ataxia telangiectasia mutated) and DNA-PK (DNA-dependent protein kinase), have been promising therapeutic targets for decades. Specific, potent DDR inhibitors (DDRi) recently entered clinical trials. Surprisingly, preclinical studies have now indicated that DDRi may stimulate anti-tumor immunity to augment immunotherapy. The mechanisms governing how DDRi could promote anti-tumor immunity are not well understood; however, early evidence suggests that they can potentiate immunogenic cell death to recruit and activate antigen-presenting cells to prime an adaptive immune response. Merkel cell carcinoma (MCC) is well suited to test these concepts. It is inherently immunogenic as ~50% of patients with advanced MCC persistently benefit from immunotherapy, making MCC one of the most responsive solid tumors. As is typical of neuroendocrine cancers, dysfunction of p53 and Rb with upregulation of Myc leads to the very rapid growth of MCC. This suggests high replication stress and susceptibility to DDRi and DNA-damaging agents. Indeed, MCC tumors are particularly radiosensitive. Given its inherent immunogenicity, cell cycle checkpoint deficiencies and sensitivity to DNA damage, MCC may be ideal for testing whether targeting the intersection of the DDR checkpoint and the immune checkpoint could help patients with immunotherapy-refractory cancers.
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49

Miyamoto, Ikuko, Ryota Ozaki, Kazuyuki Yamaguchi, Kaori Yamamoto, Atsuki Kaneko, and Takashi Ushimaru. "TORC1 regulates the DNA damage checkpoint via checkpoint protein levels." Biochemical and Biophysical Research Communications 510, no. 4 (March 2019): 629–35. http://dx.doi.org/10.1016/j.bbrc.2019.02.010.

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50

Galgoczy, David J., and David P. Toczyski. "Checkpoint Adaptation Precedes Spontaneous and Damage-Induced Genomic Instability in Yeast." Molecular and Cellular Biology 21, no. 5 (March 1, 2001): 1710–18. http://dx.doi.org/10.1128/mcb.21.5.1710-1718.2001.

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ABSTRACT Despite the fact that eukaryotic cells enlist checkpoints to block cell cycle progression when their DNA is damaged, cells still undergo frequent genetic rearrangements, both spontaneously and in response to genotoxic agents. We and others have previously characterized a phenomenon (adaptation) in which yeast cells that are arrested at a DNA damage checkpoint eventually override this arrest and reenter the cell cycle, despite the fact that they have not repaired the DNA damage that elicited the arrest. Here, we use mutants that are defective in checkpoint adaptation to show that adaptation is important for achieving the highest possible viability after exposure to DNA-damaging agents, but it also acts as an entrée into some forms of genomic instability. Specifically, the spontaneous and X-ray-induced frequencies of chromosome loss, translocations, and a repair process called break-induced replication occur at significantly reduced rates in adaptation-defective mutants. This indicates that these events occur after a cell has first arrested at the checkpoint and then adapted to that arrest. Because malignant progression frequently involves loss of genes that function in DNA repair, adaptation may promote tumorigenesis by allowing genomic instability to occur in the absence of repair.
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