Stalled Fork Rescue via Dormant Replication Origins in Unchallenged S Phase Promotes Proper Chromosome Segregation and Tumor Suppression

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....

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Published inMolecular cell Vol. 41; no. 5; pp. 543 - 553
Main Authors Kawabata, Tsuyoshi, Luebben, Spencer W., Yamaguchi, Satoru, Ilves, Ivar, Matise, Ilze, Buske, Tavanna, Botchan, Michael R., Shima, Naoko
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 04.03.2011
Subjects
Alleles
Anaphase
Animals
Cell Cycle
Cell Division
Chromosomal Instability
Chromosome Segregation
chromosomes
Cytokinesis
DNA Helicases - metabolism
DNA Replication
eukaryotic cells
fibroblasts
Fibroblasts - cytology
homozygosity
interphase
Mice
mitosis
Neoplasms - pathology
origin
Rad51 Recombinase - metabolism
Recombination, Genetic
replication
replication origin
S Phase
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Summary: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 Mcm4Chaos3 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. [Display omitted] ► An unstable MCM2-7 complex results in a loss of dormant origins in Mcm4Chaos3 cells ► A loss of dormant origins impairs stalled fork recovery in unchallenged S phase ► A loss of dormant origins increases replication intermediates in prophase ► Replication intermediates in M phase are a likely cause of chromosome instability
Bibliography:http://dx.doi.org/10.1016/j.molcel.2011.02.006
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College of Pharmacy, Division of Pharmacology and Toxicology, University of Texas, Austin, Texas 78712-1010
Faculty of veterinary medicine, Latvia university of agriculture, K. Helmana str 8 Jelgava, LV-3004, Latvia.
General Surgical Science/Education and Research Support Center, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2011.02.006