title: Deregulated origin licensing leads to chromosomal breaks by rereplication of a gapped DNA template.
abstract: Deregulated origin licensing and rereplication promote genome instability and tumorigenesis by largely elusive mechanisms. Investigating the consequences of Early mitotic inhibitor 1 (Emi1) depletion in human cells, previously associated with rereplication, we show by DNA fiber labeling that origin reactivation occurs rapidly, well before accumulation of cells with >4N DNA, and is associated with checkpoint-blind ssDNA gaps and replication fork reversal. Massive RPA chromatin loading, formation of small chromosomal fragments, and checkpoint activation occur only later, once cells complete bulk DNA replication. We propose that deregulated origin firing leads to undetected discontinuities on newly replicated DNA, which ultimately cause breakage of rereplicating forks.
authors.affiliation: Institute of Molecular Cancer Research, University of Zurich, CH-8057 Zurich, Switzerland;
authors.forename: Kai J
authors.initials: KJ
authors.lastname: Neelsen
authors.forename: Isabella M Y
authors.initials: IM
authors.lastname: Zanini
authors.forename: Sofija
authors.initials: S
authors.lastname: Mijic
authors.forename: Raquel
authors.initials: R
authors.lastname: Herrador
authors.forename: Ralph
authors.initials: R
authors.lastname: Zellweger
authors.forename: Arnab
authors.initials: A
authors.lastname: Ray Chaudhuri
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Creavin
authors.forename: J Julian
authors.initials: JJ
authors.lastname: Blow
authors.forename: Massimo
authors.initials: M
authors.lastname: Lopes
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D019457:Chromosome Breakage; D004247:DNA / Q000096:biosynthesis; D004261:DNA Replication / Q000235:genetics*; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D034741:RNA, Small Interfering / Q000378:metabolism; D018741:Replication Origin / Q000235:genetics*; D013698:Templates, Genetic
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; C498960:FBXO5 protein, human; D034741:RNA, Small Interfering; D004247:DNA
keywords: DNA replication; genome integrity; origin licensing; rereplication; tumorigenesis