Checkpoint responses to replication stalling

Inducing tolerance and preventing mutagenesis

Mihoko Kai, Teresa S F Wang

Research output: Contribution to journalArticle

Abstract

Replication mutants often exhibit a mutator phenotype characterized by point mutations, single base frameshifts, and the deletion or duplication of sequences flanked by homologous repeats. Mutation in genes encoding checkpoint proteins can significantly affect the mutator phenotype. Here, we use fission yeast (Schizosaccharomyces pombe) as a model system to discuss the checkpoint responses to replication perturbations induced by replication mutants. Checkpoint activation induced by a DNA polymerase mutant, aside from delay of mitotic entry, up-regulates the translesion polymerase DinB (Polκ). Checkpoint Rad9-Rad1-Hus1 (9-1-1) complex, which is loaded onto chromatin by the Rad17-Rfc2-5 checkpoint complex in response to replication perturbation, recruits DinB onto chromatin to generate the point mutations and single nucleotide frameshifts in the replication mutator. This chain of events reveals a novel checkpoint-induced tolerance mechanism that allows cells to cope with replication perturbation, presumably to make possible restarting stalled replication forks. Fission yeast Cds1 kinase plays an essential role in maintaining DNA replication fork stability in the face of DNA damage and replication fork stalling. Cds1 kinase is known to regulate three proteins that are implicated in maintaining replication fork stability: Mus81-Eme1, a hetero-dimeric structure-specific endonuclease complex; Rqh1, a RecQ-family helicase involved in suppressing inappropriate recombination during replication; and Rad60, a protein required for recombinational repair during replication. These Cds1-regulated proteins are thought to cooperatively prevent mutagenesis and maintain replication fork stability in cells under replication stress. These checkpoint-regulated processes allow cells to survive replication perturbation by preventing stalled replication forks from degenerating into deleterious DNA structures resulting in genomic instability and cancer development.

Original languageEnglish (US)
Pages (from-to)59-73
Number of pages15
JournalMutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
Volume532
Issue number1-2
DOIs
StatePublished - Nov 27 2003
Externally publishedYes

Fingerprint

Mutagenesis
Schizosaccharomyces
DNA Replication
Point Mutation
Chromatin
Proteins
Phosphotransferases
RecQ Helicases
Phenotype
Genomic Instability
Endonucleases
DNA-Directed DNA Polymerase
Sequence Homology
Genetic Recombination
DNA Damage
Up-Regulation
Nucleotides
Mutation
DNA
Genes

Keywords

  • Cds1
  • Checkpoints
  • DinB
  • Mus81
  • Mutator phenotype
  • Rad17
  • Translesion synthesis

ASJC Scopus subject areas

  • Health, Toxicology and Mutagenesis
  • Molecular Biology

Cite this

Checkpoint responses to replication stalling : Inducing tolerance and preventing mutagenesis. / Kai, Mihoko; Wang, Teresa S F.

In: Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, Vol. 532, No. 1-2, 27.11.2003, p. 59-73.

Research output: Contribution to journalArticle

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