Active Replication Checkpoint Drives Genome Instability in Fission Yeast mcm4 Mutant

Upon replication fork arrest, the replication checkpoint kinase Cds1 is stimulated to preserve genome integrity. Robust activation of Cds1 in response to hydroxyurea prevents the endonuclease Mus81 from cleaving the stalled replication fork inappropriately. However, we find that the response is diff...

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Bibliographic Details
Published in:Molecular and cellular biology 2020-06, Vol.40 (14)
Main Authors: Kim, Seong Min, Forsburg, Susan L.
Format: Article
Language:English
Subjects:
Cds1
Cell Cycle Checkpoints
checkpoint kinase
Checkpoint Kinase 2 - metabolism
Chk1
DNA Damage
DNA Replication
DNA, Fungal - genetics
fission yeast
genome stability
Genome, Fungal
Genomic Instability
mcm4
Minichromosome Maintenance Complex Component 4 - genetics
Minichromosome Maintenance Complex Component 4 - metabolism
Mus81
Mutation
replication stress
Schizosaccharomyces - cytology
Schizosaccharomyces - genetics
Schizosaccharomyces - metabolism
Schizosaccharomyces pombe Proteins - genetics
Schizosaccharomyces pombe Proteins - metabolism
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Summary:Upon replication fork arrest, the replication checkpoint kinase Cds1 is stimulated to preserve genome integrity. Robust activation of Cds1 in response to hydroxyurea prevents the endonuclease Mus81 from cleaving the stalled replication fork inappropriately. However, we find that the response is different in temperature-sensitive mcm4 mutants, affecting a subunit of the MCM replicative helicase. We show that Cds1 inhibition of Mus81 promotes genomic instability and allows mcm4-dg cells to evade cell cycle arrest. Cds1 regulation of Mus81 activity also contributes to the formation of the replication stress-induced DNA damage markers replication protein A (RPA) and Ku. These results identify a surprising role for Cds1 in driving DNA damage and disrupted chromosomal segregation under certain conditions of replication stress.
ISSN:1098-5549
0270-7306
1098-5549
DOI:10.1128/MCB.00033-20