Loss of rereplication control in Saccharomyces cerevisiae results in extensive DNA damage

To maintain genome stability, the entire genome of a eukaryotic cell must be replicated once and only once per cell cycle. In many organisms, multiple overlapping mechanisms block rereplication, but the consequences of deregulating these mechanisms are poorly understood. Here, we show that disruptin...

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Bibliographic Details
Published in:Molecular biology of the cell 2005-01, Vol.16 (1), p.421-432
Main Authors: Green, Brian M, Li, Joachim J
Format: Article
Language:English
Subjects:
Cell Cycle Proteins - metabolism
Cell Proliferation
Checkpoint Kinase 2
DNA Damage
DNA Replication
DNA, Fungal
Electrophoresis, Gel, Pulsed-Field
Flow Cytometry
Galactose - pharmacology
Gene Expression Regulation, Fungal
Genome
Genotype
Glucose - pharmacology
Green Fluorescent Proteins - metabolism
Immunoblotting
Metaphase
Protein Structure, Tertiary
Protein-Serine-Threonine Kinases - metabolism
Saccharomyces cerevisiae
Saccharomyces cerevisiae - genetics
Saccharomyces cerevisiae - physiology
Saccharomyces cerevisiae Proteins - metabolism
Saccharomycetales
Time Factors
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Summary:To maintain genome stability, the entire genome of a eukaryotic cell must be replicated once and only once per cell cycle. In many organisms, multiple overlapping mechanisms block rereplication, but the consequences of deregulating these mechanisms are poorly understood. Here, we show that disrupting these controls in the budding yeast Saccharomyces cerevisiae rapidly blocks cell proliferation. Rereplicating cells activate the classical DNA damage-induced checkpoint response, which depends on the BRCA1 C-terminus checkpoint protein Rad9. In contrast, Mrc1, a checkpoint protein required for recognition of replication stress, does not play a role in the response to rereplication. Strikingly, rereplicating cells accumulate subchromosomal DNA breakage products. These rapid and severe consequences suggest that even limited and sporadic rereplication could threaten the genome with significant damage. Hence, even subtle disruptions in the cell cycle regulation of DNA replication may predispose cells to the genomic instability associated with tumorigenesis.
ISSN:1059-1524
1939-4586
1059-1524
DOI:10.1091/mbc.E04-09-0833