title: Stalled fork rescue via dormant replication origins in unchallenged S phase promotes proper chromosome segregation and tumor suppression.
abstract: Eukaryotic cells license far more origins than are actually used for DNA replication, thereby generating a large number of dormant origins. Accumulating evidence suggests that such origins play a role in chromosome stability and tumor suppression, though the underlying mechanism is largely unknown. Here, we show that a loss of dormant origins results in an increased number of stalled replication forks, even in unchallenged S phase in primary mouse fibroblasts derived from embryos homozygous for the Mcm4(Chaos3) allele. We found that this allele reduces the stability of the MCM2-7 complex, but confers normal helicase activity in vitro. Despite the activation of multiple fork recovery pathways, replication intermediates in these cells persist into M phase, increasing the number of abnormal anaphase cells with lagging chromosomes and/or acentric fragments. These findings suggest that dormant origins constitute a major pathway for stalled fork recovery, contributing to faithful chromosome segregation and tumor suppression.
authors.affiliation: Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Kawabata
authors.forename: Spencer W
authors.initials: SW
authors.lastname: Luebben
authors.forename: Satoru
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Ivar
authors.initials: I
authors.lastname: Ilves
authors.forename: Ilze
authors.initials: I
authors.lastname: Matise
authors.forename: Tavanna
authors.initials: T
authors.lastname: Buske
authors.forename: Michael R
authors.initials: MR
authors.lastname: Botchan
authors.forename: Naoko
authors.initials: N
authors.lastname: Shima
mesh_terms: D000483:Alleles; D000705:Anaphase; D000818:Animals; D002453:Cell Cycle; D002455:Cell Division; D043171:Chromosomal Instability; D020090:Chromosome Segregation; D048749:Cytokinesis; D004265:DNA Helicases / Q000378:metabolism; D004261:DNA Replication; D005347:Fibroblasts / Q000166:cytology; D051379:Mice; D009369:Neoplasms / Q000473:pathology*; D051135:Rad51 Recombinase / Q000378:metabolism; D011995:Recombination, Genetic; D016196:S Phase
chemical_list: D051135:Rad51 Recombinase; C495154:Rad51 protein, mouse; D004265:DNA Helicases