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.

journal_name

Mol Cell

journal_title

Molecular cell

authors

Kawabata T,Luebben SW,Yamaguchi S,Ilves I,Matise I,Buske T,Botchan MR,Shima N

doi

10.1016/j.molcel.2011.02.006

subject

Has Abstract

pub_date

2011-03-04 00:00:00

pages

543-53

issue

5

eissn

1097-2765

issn

1097-4164

pii

S1097-2765(11)00089-X

journal_volume

41

pub_type

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