scholarly journals Yeast telomere capping protein Stn1 overrides DNA replication control through the S phase checkpoint

2009 ◽  
Vol 106 (7) ◽  
pp. 2206-2211 ◽  
Author(s):  
H. J. Gasparyan ◽  
L. Xu ◽  
R. C. Petreaca ◽  
A. E. Rex ◽  
V. Y. Small ◽  
...  
Keyword(s):  
Dna Replication ◽  
S Phase ◽  
Capping Protein ◽  
Replication Control ◽  
Telomere Capping ◽  
Yeast Telomere ◽  
S Phase Checkpoint

scholarly journals The yeast S phase checkpoint enables replicating chromosomes to bi-orient and restrain spindle extension during S phase distress

2005 ◽  
Vol 168 (7) ◽  
pp. 999-1012 ◽  
Author(s):  
Jeff Bachant ◽  
Shannon R. Jessen ◽  
Sarah E. Kavanaugh ◽  
Candida S. Fielding
Keyword(s):  
Dna Replication ◽  
Chromosome Segregation ◽  
Replication Fork ◽  
S Phase ◽  
Origin Of Replication ◽  
Independent Manner ◽  
Checkpoint Signaling ◽  
Hydroxyurea Treatment ◽  
Chromatid Cohesion ◽  
S Phase Checkpoint

The budding yeast S phase checkpoint responds to hydroxyurea-induced nucleotide depletion by preventing replication fork collapse and the segregation of unreplicated chromosomes. Although the block to chromosome segregation has been thought to occur by inhibiting anaphase, we show checkpoint-defective rad53 mutants undergo cycles of spindle extension and collapse after hydroxyurea treatment that are distinct from anaphase cells. Furthermore, chromatid cohesion, whose dissolution triggers anaphase, is dispensable for S phase checkpoint arrest. Kinetochore–spindle attachments are required to prevent spindle extension during replication blocks, and chromosomes with two centromeres or an origin of replication juxtaposed to a centromere rescue the rad53 checkpoint defect. These observations suggest that checkpoint signaling is required to generate an inward force involved in maintaining preanaphase spindle integrity during DNA replication distress. We propose that by promoting replication fork integrity under these conditions Rad53 ensures centromere duplication. Replicating chromosomes can then bi-orient in a cohesin-independent manner to restrain untimely spindle extension.

scholarly journals Divergent S Phase Checkpoint Activation Arising from Prereplicative Complex Deficiency Controls Cell Survival

2009 ◽  
Vol 20 (17) ◽  
pp. 3953-3964 ◽  
Author(s):  
Eric Lau ◽  
Gary G. Chiang ◽  
Robert T. Abraham ◽  
Wei Jiang
Keyword(s):  
Dna Replication ◽  
Cancer Cells ◽  
S Phase ◽  
Checkpoint Control ◽  
Multiple Cancer ◽  
Checkpoint Activation ◽  
Diploid Cells ◽  
Prereplicative Complex ◽  
Stress Damage ◽  
S Phase Checkpoint

The DNA replication machinery plays additional roles in S phase checkpoint control, although the identities of the replication proteins involved in checkpoint activation remain elusive. Here, we report that depletion of the prereplicative complex (pre-RC) protein Cdc6 causes human nontransformed diploid cells to arrest nonlethally in G1-G1/S and S phase, whereas multiple cancer cell lines undergo G1-G1/S arrest and cell death. These divergent phenotypes are dependent on the activation, or lack thereof, of an ataxia telangiectasia and Rad3-related (ATR)-dependent S phase checkpoint that inhibits replication fork progression. Although pre-RC deficiency induces chromatin structural alterations in both nontransformed and cancer cells that normally lead to ATR checkpoint activation, the sensor mechanisms in cancer cells seem to be compromised such that higher levels of DNA replication stress/damage are required to trigger checkpoint response. Our results suggest that therapy-induced disruption of pre-RC function might exert selective cytotoxic effects on tumor cells in human patients.

scholarly journals Mrc1 and DNA Polymerase ɛ Function Together in Linking DNA Replication and the S Phase Checkpoint

2008 ◽  
Vol 32 (1) ◽  
pp. 106-117 ◽  
Author(s):  
Huiqiang Lou ◽  
Makiko Komata ◽  
Yuki Katou ◽  
Zhiyun Guan ◽  
Clara C. Reis ◽  
...  
Keyword(s):  
Dna Replication ◽  
Dna Polymerase ◽  
S Phase ◽  
S Phase Checkpoint

scholarly journals Activation of the DNA Damage Checkpoint in Mutants Defective in DNA Replication Initiation

2008 ◽  
Vol 19 (10) ◽  
pp. 4374-4382 ◽  
Author(s):  
Ling Yin ◽  
Alexandra Monica Locovei ◽  
Gennaro D'Urso
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Replication Fork ◽  
S Phase ◽  
Replication Initiation ◽  
Dna Damage Checkpoint ◽  
Origin Firing ◽  
Dna Replication Initiation ◽  
Fork Stalling ◽  
S Phase Checkpoint

In the fission yeast, Schizosaccharomyces pombe, blocks to DNA replication elongation trigger the intra-S phase checkpoint that leads to the activation of the Cds1 kinase. Cds1 is required to both prevent premature entry into mitosis and to stabilize paused replication forks. Interestingly, although Cds1 is essential to maintain the viability of mutants defective in DNA replication elongation, mutants defective in DNA replication initiation require the Chk1 kinase. This suggests that defects in DNA replication initiation can lead to activation of the DNA damage checkpoint independent of the intra-S phase checkpoint. This might result from reduced origin firing that leads to an increase in replication fork stalling or replication fork collapse that activates the G2 DNA damage checkpoint. We refer to the Chk1-dependent, Cds1-independent phenotype as the rid phenotype (for replication initiation defective). Chk1 is active in rid mutants, and rid mutant viability is dependent on the DNA damage checkpoint, and surprisingly Mrc1, a protein required for activation of Cds1. Mutations in Mrc1 that prevent activation of Cds1 have no effect on its ability to support rid mutant viability, suggesting that Mrc1 has a checkpoint-independent role in maintaining the viability of mutants defective in DNA replication initiation.

scholarly journals Activation of mammalian Chk1 during DNA replication arrest

2001 ◽  
Vol 154 (5) ◽  
pp. 913-924 ◽  
Author(s):  
Carmen Feijoo ◽  
Clare Hall-Jackson ◽  
Rong Wu ◽  
David Jenkins ◽  
Jane Leitch ◽  
...  
Keyword(s):  
Dna Replication ◽  
Mammalian Cells ◽  
S Phase ◽  
Global Pattern ◽  
Origin Firing ◽  
Replication Arrest ◽  
Molecule Inhibitor ◽  
Replication Block ◽  
Phase Progression ◽  
S Phase Checkpoint

Checkpoints maintain order and fidelity in the cell cycle by blocking late-occurring events when earlier events are improperly executed. Here we describe evidence for the participation of Chk1 in an intra-S phase checkpoint in mammalian cells. We show that both Chk1 and Chk2 are phosphorylated and activated in a caffeine-sensitive signaling pathway during S phase, but only in response to replication blocks, not during normal S phase progression. Replication block–induced activation of Chk1 and Chk2 occurs normally in ataxia telangiectasia (AT) cells, which are deficient in the S phase response to ionizing radiation (IR). Resumption of synthesis after removal of replication blocks correlates with the inactivation of Chk1 but not Chk2. Using a selective small molecule inhibitor, cells lacking Chk1 function show a progressive change in the global pattern of replication origin firing in the absence of any DNA replication. Thus, Chk1 is apparently necessary for an intra-S phase checkpoint, ensuring that activation of late replication origins is blocked and arrested replication fork integrity is maintained when DNA synthesis is inhibited.

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