title: Multiple regulatory mechanisms to inhibit untimely initiation of DNA replication are important for stable genome maintenance.
abstract: Genomic instability is a hallmark of human cancer cells. To prevent genomic instability, chromosomal DNA is faithfully duplicated in every cell division cycle, and eukaryotic cells have complex regulatory mechanisms to achieve this goal. Here, we show that untimely activation of replication origins during the G1 phase is genotoxic and induces genomic instability in the budding yeast Saccharomyces cerevisiae. Our data indicate that cells preserve a low level of the initiation factor Sld2 to prevent untimely initiation during the normal cell cycle in addition to controlling the phosphorylation of Sld2 and Sld3 by cyclin-dependent kinase. Although untimely activation of origin is inhibited on multiple levels, we show that deregulation of a single pathway can cause genomic instability, such as gross chromosome rearrangements (GCRs). Furthermore, simultaneous deregulation of multiple pathways causes an even more severe phenotype. These findings highlight the importance of having multiple inhibitory mechanisms to prevent the untimely initiation of chromosome replication to preserve stable genome maintenance over generations in eukaryotes.
authors.affiliation: Division of Microbial Genetics, National Institute of Genetics, Mishima, Japan. setanaka@lab.nig.ac.jp
authors.forename: Seiji
authors.initials: S
authors.lastname: Tanaka
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Araki
mesh_terms: D018797:Cell Cycle Proteins / Q000378:metabolism; D002869:Chromosome Aberrations; D053903:DNA Breaks, Double-Stranded; D004261:DNA Replication / Q000235:genetics*; D016193:G1 Phase / Q000235:genetics; D015966:Gene Expression Regulation, Fungal; D015321:Gene Rearrangement; D016681:Genome, Fungal / Q000235:genetics*; D042822:Genomic Instability / Q000235:genetics; D018741:Replication Origin / Q000235:genetics*; D016196:S Phase / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C097185:DPB11 protein, S cerevisiae; C115043:SLD2 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins