scholarly journals The Schizosaccharomyces pombe S-Phase Checkpoint Differentiates Between Different Types of DNA Damage

Genetics ◽  
1998 ◽  
Vol 149 (4) ◽  
pp. 1729-1737 ◽  
Author(s):  
Nicholas Rhind ◽  
Paul Russell
Keyword(s):  
Dna Damage ◽  
Schizosaccharomyces Pombe ◽  
S Phase ◽  
Dna Damage Checkpoint ◽  
Haploid Cell ◽  
Γ Irradiation ◽  
Replication Checkpoint ◽  
Checkpoint Proteins ◽  
Base Modification ◽  
Different Types

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.

scholarly journals p21 Inhibits Cdk1 in the Absence of Cdk2 to Maintain the G1/S Phase DNA Damage Checkpoint

2008 ◽  
Vol 19 (1) ◽  
pp. 65-77 ◽  
Author(s):  
Ande Satyanarayana ◽  
Mary Beth Hilton ◽  
Philipp Kaldis
Keyword(s):  
Dna Damage ◽  
Liver Cells ◽  
S Phase ◽  
Dna Damage Checkpoint ◽  
Regenerating Liver ◽  
Γ Irradiation ◽  
Embryonic Fibroblasts ◽  
Repair Activity ◽  
Lethal Irradiation

Cdk1 was proposed to compensate for the loss of Cdk2. Here we present evidence that this is possible due to premature translocation of Cdk1 from the cytoplasm to the nucleus in the absence of Cdk2. We also investigated the consequence of loss of Cdk2 on the maintenance of the G1/S DNA damage checkpoint. Cdk2−/− mouse embryonic fibroblasts in vitro as well as regenerating liver cells after partial hepatectomy (PH) in Cdk2−/− mice, arrest promptly at the G1/S checkpoint in response to γ-irradiation due to activation of p53 and p21 inhibiting Cdk1. Furthermore re-entry into S phase after irradiation was delayed in Cdk2−/− cells due to prolonged and impaired DNA repair activity. In addition, Cdk2−/− mice were more sensitive to lethal irradiation compared to wild-type and displayed delayed resumption of DNA replication in regenerating liver cells. Our results suggest that the G1/S DNA damage checkpoint is intact in the absence of Cdk2, but Cdk2 is important for proper repair of the damaged DNA.

scholarly journals Mechanism of Caffeine-Induced Checkpoint Override in Fission Yeast

2000 ◽  
Vol 20 (12) ◽  
pp. 4288-4294 ◽  
Author(s):  
Bettina A. Moser ◽  
Jean-Marc Brondello ◽  
Beth Baber-Furnari ◽  
Paul Russell
Keyword(s):  
Dna Damage ◽  
Schizosaccharomyces Pombe ◽  
Fission Yeast ◽  
Protein Kinases ◽  
Molecular Target ◽  
S Phase ◽  
Dna Damage Checkpoint ◽  
Mitotic Checkpoints ◽  
Direct Activation

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.

scholarly journals Poly(ADP-ribose) Binds to Specific Domains in DNA Damage Checkpoint Proteins

2000 ◽  
Vol 275 (52) ◽  
pp. 40974-40980 ◽  
Author(s):  
Jutta M. Pleschke ◽  
Hanna E. Kleczkowska ◽  
Mark Strohm ◽  
Felix R. Althaus
Keyword(s):  
Dna Damage ◽  
Dna Damage Checkpoint ◽  
Checkpoint Proteins

MDC1 is required for the intra-S-phase DNA damage checkpoint

Nature ◽  
2003 ◽  
Vol 421 (6926) ◽  
pp. 952-956 ◽  
Author(s):  
Michal Goldberg ◽  
Manuel Stucki ◽  
Jacob Falck ◽  
Damien D'Amours ◽  
Dinah Rahman ◽  
...  
Keyword(s):  
Dna Damage ◽  
S Phase ◽  
Dna Damage Checkpoint

scholarly journals Recruitment of DNA Damage Checkpoint Proteins to Damage in Transcribed and Nontranscribed Sequences

2006 ◽  
Vol 26 (1) ◽  
pp. 39-49 ◽  
Author(s):  
Guochun Jiang ◽  
Aziz Sancar
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Excision Repair ◽  
Dna Lesions ◽  
Human Cells ◽  
Dna Damage Checkpoint ◽  
Damage Site ◽  
Checkpoint Response ◽  
Checkpoint Proteins ◽  
Transcription Complexes

ABSTRACT We developed a chromatin immunoprecipitation method for analyzing the binding of repair and checkpoint proteins to DNA base lesions in any region of the human genome. Using this method, we investigated the recruitment of DNA damage checkpoint proteins RPA, Rad9, and ATR to base damage induced by UV and acetoxyacetylaminofluorene in transcribed and nontranscribed regions in wild-type and excision repair-deficient human cells in G1 and S phases of the cell cycle. We find that all 3 damage sensors tested assemble at the site or in the vicinity of damage in the absence of DNA replication or repair and that transcription enhances recruitment of checkpoint proteins to the damage site. Furthermore, we find that UV irradiation of human cells defective in excision repair leads to phosphorylation of Chk1 kinase in both G1 and S phase of the cell cycle, suggesting that primary DNA lesions as well as stalled transcription complexes may act as signals to initiate the DNA damage checkpoint response.

scholarly journals Phosphorylation of the Budding Yeast 9-1-1 Complex Is Required for Dpb11 Function in the Full Activation of the UV-Induced DNA Damage Checkpoint

2008 ◽  
Vol 28 (15) ◽  
pp. 4782-4793 ◽  
Author(s):  
Fabio Puddu ◽  
Magda Granata ◽  
Lisa Di Nola ◽  
Alessia Balestrini ◽  
Gabriele Piergiovanni ◽  
...  
Keyword(s):  
Dna Damage ◽  
Budding Yeast ◽  
Dna Damage Checkpoint ◽  
Checkpoint Activation ◽  
Checkpoint Response ◽  
Checkpoint Proteins ◽  
M Phase ◽  
Mutant Cells ◽  
Full Activation

ABSTRACT Following genotoxic insults, eukaryotic cells trigger a signal transduction cascade known as the DNA damage checkpoint response, which involves the loading onto DNA of an apical kinase and several downstream factors. Chromatin modifications play an important role in recruiting checkpoint proteins. In budding yeast, methylated H3-K79 is bound by the checkpoint factor Rad9. Loss of Dot1 prevents H3-K79 methylation, leading to a checkpoint defect in the G1 phase of the cell cycle and to a reduction of checkpoint activation in mitosis, suggesting that another pathway contributes to Rad9 recruitment in M phase. We found that the replication factor Dpb11 is the keystone of this second pathway. dot1Δ dpb11-1 mutant cells are sensitive to UV or Zeocin treatment and cannot activate Rad53 if irradiated in M phase. Our data suggest that Dpb11 is held in proximity to damaged DNA through an interaction with the phosphorylated 9-1-1 complex, leading to Mec1-dependent phosphorylation of Rad9. Dpb11 is also phosphorylated after DNA damage, and this modification is lost in a nonphosphorylatable ddc1-T602A mutant. Finally, we show that, in vivo, Dpb11 cooperates with Dot1 in promoting Rad9 phosphorylation but also contributes to the full activation of Mec1 kinase.

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