scholarly journals Onset of the DNA Replication Checkpoint in the Early Drosophila Embryo

Genetics ◽  
2006 ◽  
Vol 175 (2) ◽  
pp. 567-584 ◽  
Author(s):  
Justin Crest ◽  
Nathan Oxnard ◽  
Jun-Yuan Ji ◽  
Gerold Schubiger
Keyword(s):  
Dna Replication ◽  
Drosophila Embryo ◽  
Replication Checkpoint ◽  
Early Drosophila Embryo ◽  
Dna Replication Checkpoint

Overlapping Roles of the Spindle Assembly and DNA Damage Checkpoints in the Cell-Cycle Response to Altered Chromosomes in Saccharomyces cerevisiae

Genetics ◽  
2002 ◽  
Vol 161 (2) ◽  
pp. 521-534
Author(s):  
Peter M Garber ◽  
Jasper Rine
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Spindle Checkpoint ◽  
Dna Lesions ◽  
Replication Proteins ◽  
Replication Checkpoint ◽  
Dna Damage Checkpoints ◽  
Dna Replication Checkpoint ◽  
Mcm Proteins ◽  
Stalled Replication Forks

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.

scholarly journals The Direct Binding of Mrc1, a Checkpoint Mediator, to Mcm6, a Replication Helicase, Is Essential for the Replication Checkpoint against Methyl Methanesulfonate-Induced Stress

2009 ◽  
Vol 29 (18) ◽  
pp. 5008-5019 ◽  
Author(s):  
Makiko Komata ◽  
Masashige Bando ◽  
Hiroyuki Araki ◽  
Katsuhiko Shirahige
Keyword(s):  
Amino Acid ◽  
Dna Replication ◽  
Terminal Region ◽  
Methyl Methanesulfonate ◽  
Checkpoint Activation ◽  
Replication Checkpoint ◽  
Hydroxyurea Treatment ◽  
Dna Replication Checkpoint ◽  
Direct Binding

ABSTRACT Mrc1 plays a role in mediating the DNA replication checkpoint. We surveyed replication elongation proteins that interact directly with Mrc1 and identified a replicative helicase, Mcm6, as a specific Mrc1-binding protein. The central portion of Mrc1, containing a conserved coiled-coil region, was found to be essential for interaction with the 168-amino-acid C-terminal region of Mcm6, and introduction of two amino acid substitutions in this C-terminal region abolished the interaction with Mrc1 in vivo. An mcm6 mutant bearing these substitutions showed a severe defect in DNA replication checkpoint activation in response to stress caused by methyl methanesulfonate. Interestingly, the mutant did not show any defect in DNA replication checkpoint activation in response to hydroxyurea treatment. The phenotype of the mcm6 mutant was suppressed when the mutant protein was physically fused with Mrc1. These results strongly suggest for the first time that an Mcm helicase acts as a checkpoint sensor for methyl methanesulfonate-induced DNA damage through direct binding to the replication checkpoint mediator Mrc1.

scholarly journals Stockpiling of Cdc25 during a DNA replication checkpoint arrest in Schizosaccharomyces pombe.

1996 ◽  
Vol 16 (1) ◽  
pp. 86-93 ◽  
Author(s):  
R Kovelman ◽  
P Russell
Keyword(s):  
Dna Replication ◽  
Schizosaccharomyces Pombe ◽  
Replication Checkpoint ◽  
Activation Assay ◽  
M Phase ◽  
Dna Replication Checkpoint ◽  
High Level ◽  
Tyrosyl Phosphorylation ◽  
In Cells

The DNA replication checkpoint couples the onset of mitosis with the completion of S phase. It is clear that in the fission yeast Schizosaccharomyces pombe, operation of this checkpoint requires maintenance of the inhibitory tyrosyl phosphorylation of Cdc2. Cdc25 phosphatase induces mitosis by dephosphorylating tyrosine 15 of Cdc2. In this report, Cdc25 is shown to accumulate to a very high level in cells arrested in S. This shows that mechanisms which modulate the abundance of Cdc25 are unconnected to the DNA replication checkpoint. Using a Cdc2/cyclin B activation assay, we found that Cdc25 activity increased approximately 10-fold during transit through M phase. Cdc25 was activated by phosphorylations that were dependent on Cdc2 activity in vivo. Cdc25 activation was suppressed in cells arrested in G1 and S. However, Cdc25 was more highly modified and appeared to be somewhat more active in S than in G1. This finding might be connected to the fact that progression from G1 to S increases the likelihood that constitutive Cdc25 overproduction will cause inappropriate mitosis.

scholarly journals Therapeutic vulnerability to PARP1,2 inhibition in RB1-mutant osteosarcoma

2021 ◽  
Author(s):  
Georgia Zoumpoulidou ◽  
Carlos Alvarez Mendoza ◽  
Caterina Mancusi ◽  
Ritika-Mahmuda Ahmed ◽  
Milly Denman ◽  
...  
Keyword(s):  
Dna Replication ◽  
Loss Of Function ◽  
Genome Maintenance ◽  
Treatment Results ◽  
Replication Checkpoint ◽  
Dna Replication Checkpoint ◽  
Extensive Cell Death ◽  
Extensive Cell ◽  
Key Drivers ◽  
Rapid Activation

Abstract Loss-of-function mutations in the RB1 tumour suppressor are key drivers in cancer, including osteosarcoma. RB1 loss-of-function compromises genome-maintenance and hence could yield vulnerability to therapeutics targeting such processes. Here we demonstrate selective hypersensitivity to clinically-approved inhibitors of Poly-ADP-Polymerase1,2 inhibitors (PARPi) in RB1-mutated cancer cells including an extended panel of osteosarcoma-derived lines. PARPi treatment results in extensive cell death in RB1-mutated backgrounds and prolongs survival of mice carrying human RB1-mutated osteosarcoma grafts. PARPi sensitivity is not associated with canonical homologous recombination defect (HRd) signatures, which predict PARPi sensitivity in cancers with BRCA1,2 loss, but is accompanied by rapid activation of DNA replication checkpoint signalling, and active DNA replication is a prerequisite for sensitivity. Importantly, sensitivity in backgrounds with natural or engineered RB1 loss surpasses that seen in BRCA-mutated backgrounds where PARPi have established clinical benefit. Our work provides evidence that PARPi sensitivity extends beyond cancers identifiable by HRd and advocates PARP1,2 inhibition as a novel, personalised strategy for RB1-mutated osteosarcoma and other cancers.

scholarly journals DNA Replication Checkpoint Control Mediated by the Spindle Checkpoint Protein Mad2p in Fission Yeast

2004 ◽  
Vol 279 (45) ◽  
pp. 47372-47378 ◽  
Author(s):  
Izumi Sugimoto ◽  
Hiroshi Murakami ◽  
Yuko Tonami ◽  
Akihiko Moriyama ◽  
Makoto Nakanishi
Keyword(s):  
Dna Replication ◽  
Fission Yeast ◽  
Spindle Checkpoint ◽  
Checkpoint Control ◽  
Replication Checkpoint ◽  
Checkpoint Protein ◽  
Dna Replication Checkpoint
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