Strand break-induced replication fork collapse leads to C-circles, C-overhangs and telomeric recombination
Strand break-induced replication fork collapse leads to C-circles, C-overhangs and telomeric recombination
复制标题
链断裂诱导的复制叉塌陷导致 C 环、C 突出和端粒重组
DOI：
10.1371/journal.pgen.1007925
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发表时间：
2019-02-01
期刊：
影响因子：
4.5
通讯作者：
Zhao, Yong
中科院分区：
文献类型：
--
作者：
Zhang, Tianpeng;Zhang, Zepeng;Zhao, Yong
端粒酶非依赖性ALT（端粒选择性延长）细胞具有高频率的端粒同源重组（HR）、富含c的染色体外环（C-circles）和富含c的末端5'悬垂（c -overhang）等特征。然而，其潜在机制尚不清楚。在这里，我们表明当端粒链断裂诱导复制叉崩溃时，c -环和c -悬垂都形成。我们发现内源性DNA断裂主要发生在ALT细胞的端粒富c链上，导致复制叉崩溃的频率很高。折叠叉可以通过复制叉回归修复，导致端粒同源重组，而未修复的分叉则分别在合成链的滞后和前导处转化为c -环和c -悬垂。同时，ALT的多个标志被激发，表明链断裂诱导的复制应激是ALT的基础。这些发现为端粒HR和c -环和c -悬垂的生物发生提供了分子基础，从而暗示了解决链断裂诱导的端粒复制缺陷的具体机制。
Telomerase-independent ALT (alternative lengthening of telomeres) cells are characterized by high frequency of telomeric homologous recombination (HR), C-rich extrachromosomal circles (C-circles) and C-rich terminal 5' overhangs (C-overhangs). However, underlying mechanism is poorly understood. Here, we show that both C-circle and C-overhang form when replication fork collapse is induced by strand break at telomeres. We find that endogenous DNA break predominantly occur on C-rich strand of telomeres in ALT cells, resulting in high frequency of replication fork collapse. While collapsed forks could be rescued by replication fork regression leading to telomeric homologous recombination, those unresolved are converted to C-circles and C-overhang at lagging and leading synthesized strand, respectively. Meanwhile, multiple hallmarks of ALT are provoked, suggesting that strand break-induced replication stress underlies ALT. These findings provide a molecular basis underlying telomeric HR and biogenesis of C-circle and C-overhang, thus implicating the specific mechanism to resolve strand break-induced replication defect at telomeres in ALT cells.