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Mol Cell. 2011 Mar 4;41(5):543-53. doi: 10.1016/j.molcel.2011.02.006.

Stalled fork rescue via dormant replication origins in unchallenged S phase promotes proper chromosome segregation and tumor suppression.

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1
Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA.

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.

PMID:
21362550
PMCID:
PMC3062258
DOI:
10.1016/j.molcel.2011.02.006
[Indexed for MEDLINE]
Free PMC Article
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