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Schizosaccharomyces pombe checkpoint response to DNA interstrand cross-links.
- Source :
-
Molecular and cellular biology [Mol Cell Biol] 2003 Jul; Vol. 23 (13), pp. 4728-37. - Publication Year :
- 2003
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Abstract
- Drugs that produce covalent interstrand cross-links (ICLs) in DNA remain central to the treatment of cancer, but the cell cycle checkpoints activated by ICLs have received little attention. We have used the fission yeast, Schizosaccharomyces pombe, to elucidate the checkpoint responses to the ICL-inducing anticancer drugs nitrogen mustard and mitomycin C. First we confirmed that the repair pathways acting on ICLs in this yeast are similar to those in the main organisms studied to date (Escherichia coli, budding yeast, and mammalian cells), principally nucleotide excision repair and homologous recombination. We also identified and disrupted the S. pombe homologue of the Saccharomyces cerevisiae SNM1/PSO2 ICL repair gene and found that this activity is required for normal resistance to cross-linking agents, but not other forms of DNA damage. Survival and biochemical analysis indicated a key role for the "checkpoint Rad" family acting through the chk1-dependent DNA damage checkpoint in the ICL response. Rhp9-dependent phosphorylation of Chk1 correlates with G(2) arrest following ICL induction. In cells able to bypass the G(2) block, a second-cycle (S-phase) arrest was observed. Only a transient activation of the Cds1 DNA replication checkpoint factor occurs following ICL formation in wild-type cells, but this is increased and persists in G(2) arrest-deficient mutants. This likely reflects the fraction of cells escaping the G(2) damage checkpoint and arresting in the subsequent S phase due to ICL replication blocks. Disruption of cds1 confers increased resistance to ICLs, suggesting that this second-cycle S-phase arrest might be a lethal event.
- Subjects :
- Camptothecin pharmacology
Cell Survival
Checkpoint Kinase 2
Cisplatin pharmacology
DNA drug effects
DNA radiation effects
DNA Damage
DNA Repair
Dose-Response Relationship, Drug
Dose-Response Relationship, Radiation
Enzyme Inhibitors pharmacology
G2 Phase
Hydroxyurea pharmacology
Mitomycin pharmacology
Nucleic Acid Synthesis Inhibitors pharmacology
Phosphorylation
Protein Kinases metabolism
Radiation-Sensitizing Agents pharmacology
Recombination, Genetic
S Phase
Schizosaccharomyces pombe Proteins
Temperature
Time Factors
Cross-Linking Reagents pharmacology
Protein Serine-Threonine Kinases
Schizosaccharomyces genetics
Schizosaccharomyces metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0270-7306
- Volume :
- 23
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- Molecular and cellular biology
- Publication Type :
- Academic Journal
- Accession number :
- 12808110
- Full Text :
- https://doi.org/10.1128/MCB.23.13.4728-4737.2003