A concomitant loss of dormant origins and FANCC exacerbates genome instability by impairing DNA replication fork progression.
A concomitant loss of dormant origins and FANCC exacerbates genome instability by impairing DNA replication fork progression.
复制标题
伴随着休眠起源和狂热的丧失，通过损害DNA复制叉进展来加剧基因组的不稳定性。
DOI：
10.1093/nar/gku170
复制
发表时间：
2014-05
影响因子：
14.9
通讯作者：
Shima N
中科院分区：
文献类型：
--
作者：
Luebben SW;Kawabata T;Johnson CS;O'Sullivan MG;Shima N
越来越多的证据表明，休眠的DNA复制起点在恢复停滞的叉子中起着重要作用。但是，它们与其他分叉恢复机制的功能交互尚未经过测试。我们先前报道了在肿瘤易感小鼠模型（Mcm 4chaos 3）中Fanconi贫血（FA）通路的内在激活，其中休眠起源丧失了60%。为了进一步理解这一点，我们在Mcm 4chaos 3背景中引入了一个编码FA核心复合物成员的Fancc（Fancc−）的无效等位基因。原代胚胎成纤维细胞Mcm 4chaos 3和Fancc−双纯合子（Mcm 4chaos 3/chaos 3;Fancc−/−）表现出显着增加水平的标志物停滞/塌陷叉相比，任何一个单一的纯合子。有趣的是，休眠起源的丢失也增加了复制延迟到前期的位点的数量，而不管FA通路的激活。这些复制缺陷与Mcm 4chaos 3/chaos 3;Fancc−/−细胞中基因组不稳定性水平的显著升高相吻合，导致Mcm 4chaos 3/chaos 3;Fancc−/−小鼠的围产期致死率较高，存活小鼠的肿瘤发生加速。总之，这些发现揭示了休眠起源在复制完成中的特殊作用，同时还确定了休眠起源和FA通路在维持分叉进展，基因组稳定性，正常发育和肿瘤抑制方面的重要功能重叠。
Accumulating evidence suggests that dormant DNA replication origins play an important role in the recovery of stalled forks. However, their functional interactions with other fork recovery mechanisms have not been tested. We previously reported intrinsic activation of the Fanconi anemia (FA) pathway in a tumor-prone mouse model (Mcm4chaos3) with a 60% loss of dormant origins. To understand this further, we introduced a null allele of Fancc (Fancc−), encoding a member of the FA core complex, into the Mcm4chaos3 background. Primary embryonic fibroblasts double homozygous for Mcm4chaos3 and Fancc− (Mcm4chaos3/chaos3;Fancc−/−) showed significantly increased levels of markers of stalled/collapsed forks compared to either single homozygote. Interestingly, a loss of dormant origins also increased the number of sites in which replication was delayed until prophase, regardless of FA pathway activation. These replication defects coincided with substantially elevated levels of genome instability in Mcm4chaos3/chaos3;Fancc−/− cells, resulting in a high rate of perinatal lethality of Mcm4chaos3/chaos3;Fancc−/− mice and the accelerated tumorigenesis of surviving mice. Together, these findings uncover a specialized role of dormant origins in replication completion while also identifying important functional overlaps between dormant origins and the FA pathway in maintaining fork progression, genome stability, normal development and tumor suppression.
登录
查看更多内容
影响因子：
9.8
作者：
Bogliolo, Massimo;Schuster, Beatrice;Surralles, Jordi
通讯作者：
Surralles, Jordi
影响因子：
64.5
作者：
Casper, AM;Nghiem, P;Glover, TW
通讯作者：
Glover, TW
影响因子：
15.9
作者：
Gineau, Laure;Cognet, Celine;Jouanguy, Emmanuelle
通讯作者：
Jouanguy, Emmanuelle
影响因子：
15.9
作者：
Hughes, Claire R.;Guasti, Leonardo;Metherell, Louise A.
通讯作者：
Metherell, Louise A.
影响因子：
4.8
作者：
Edwards, MC;Tutter, AV;Walter, JC
通讯作者：
Walter, JC