Stalled fork rescue via dormant replication origins in unchallenged S phase promotes proper chromosome segregation and tumor suppression.
Stalled fork rescue via dormant replication origins in unchallenged S phase promotes proper chromosome segregation and tumor suppression.
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DOI：
10.1016/j.molcel.2011.02.006
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发表时间：
2011-03-04
期刊：
影响因子：
16
通讯作者：
Shima N
中科院分区：
文献类型：
--
作者：
Kawabata T;Luebben SW;Yamaguchi S;Ilves I;Matise I;Buske T;Botchan MR;Shima N
真核细胞许可的起始点远远多于实际用于DNA复制的起始点，从而产生大量的休眠起始点。越来越多的证据表明，这种起源在染色体稳定性和肿瘤抑制中发挥作用，尽管其潜在机制在很大程度上尚不清楚。在这里，我们表明，休眠的起源的损失导致停滞的复制叉的数量增加，即使在未受到挑战的S期在原代小鼠成纤维细胞来自纯合子的Mcm 4Chaos 3等位基因的胚胎。我们发现，该等位基因降低了MCM 2 -7复合物的稳定性，但在体外赋予正常的解旋酶活性。尽管激活了多个叉恢复途径，但这些细胞中的复制中间体持续到M期，增加了具有落后染色体和/或无着丝粒片段的异常后期细胞的数量。这些发现表明，休眠起源构成了停滞叉恢复的主要途径，有助于忠实的染色体分离和肿瘤抑制。
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.
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影响因子：
64.5
作者：
Casper, AM;Nghiem, P;Glover, TW
通讯作者：
Glover, TW
影响因子：
8
作者：
Kunnev D;Rusiniak ME;Kudla A;Freeland A;Cady GK;Pruitt SC
通讯作者：
Pruitt SC
DOI：
10.1073/pnas.1232231100
发表时间：
2003-05-27
影响因子：
11.1
作者：
Hendricks, CA;Almeida, KH;Engelward, BP
通讯作者：
Engelward, BP
影响因子：
11.5
作者：
Ha, SA;Shin, SM;Kim, JW
通讯作者：
Kim, JW
影响因子：
16.8
作者：
Davies, Sally L.;North, Phillip S.;Hickson, Ian D.
通讯作者：
Hickson, Ian D.