Open AccessActive Replication Checkpoint Drives Genome Instability in Fission Yeast mcm4 Mutant
Author(s) -
Seong M. Kim,
Susan L. Forsburg
Publication year - 2020
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.00033-20
Subject(s) - biology , control of chromosome duplication , origin recognition complex , pre replication complex , dna replication , g2 m dna damage checkpoint , genome instability , licensing factor , dna re replication , cell cycle checkpoint , eukaryotic dna replication , minichromosome maintenance , microbiology and biotechnology , dna replication factor cdt1 , dna damage , genetics , replication factor c , helicase , origin of replication , cell cycle , dna , gene , rna
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.