Role of RPA Phosphorylation in the ATR-Dependent G2 Cell Cycle Checkpoint.
Role of RPA Phosphorylation in the ATR-Dependent G2 Cell Cycle Checkpoint.
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RPA磷酸化在ATR依赖的G2细胞周期检查点中的作用
作者：
细胞通过启动DSB修复和确保细胞周期检查点来响应DNA双链断裂。对DSB修复的主要响应者是非同源末端连接，这是一种易错修复途径。然而，当在细胞周期的G2期DNA复制后产生DSB时，第二个DSB修复途径，同源重组，可以发挥作用。ATM和ATR对DSB诱导的DSB修复和检查点反应都很重要。ATM和ATR一起工作的一种方法是通过DSB的DNA末端切除。作为DNA末端切除的读出和标记，RPA在响应于DSB的RPA 32的N-末端的Ser 4/Ser 8处被磷酸化。在这里，RPA 32 Ser 4/Ser 8磷酸化在响应DNA损伤，特别是在细胞周期的S期到G2期的意义，进行了检查。G2期同步化细胞中RPA 32 Ser 4/Ser 8磷酸化对于染色质上TopBP 1和Rad 9积累的增加以及ATR依赖性G2检查点的完全激活是必需的。此外，我们的数据表明，RPA Ser 4/Ser 8磷酸化调节ATM依赖的KAP-1磷酸化和Rad 51染色质加载在G2细胞。通过RPA Ser 4/Ser 8的磷酸化，ATM在G2期检查点反应中作为ATR的伴侣，通过靶向RPA 32 Ser 4/Ser 8调节关键下游事件，包括Rad 9，TopBP 1磷酸化和KAP-1磷酸化/激活。
Cells respond to DNA double-strand breaks by initiating DSB repair and ensuring a cell cycle checkpoint. The primary responder to DSB repair is non-homologous end joining, which is an error-prone repair pathway. However, when DSBs are generated after DNA replication in the G2 phase of the cell cycle, a second DSB repair pathway, homologous recombination, can come into action. Both ATM and ATR are important for DSB-induced DSB repair and checkpoint responses. One method of ATM and ATR working together is through the DNA end resection of DSBs. As a readout and marker of DNA end resection, RPA is phosphorylated at Ser4/Ser8 of the N-terminus of RPA32 in response to DSBs. Here, the significance of RPA32 Ser4/Ser8 phosphorylation in response to DNA damage, specifically in the S phase to G2 phase of the cell cycle, is examined. RPA32 Ser4/Ser8 phosphorylation in G2 synchronized cells is necessary for increases in TopBP1 and Rad9 accumulation on chromatin and full activation of the ATR-dependent G2 checkpoint. In addition, our data suggest that RPA Ser4/Ser8 phosphorylation modulates ATM-dependent KAP-1 phosphorylation and Rad51 chromatin loading in G2 cells. Through the phosphorylation of RPA Ser4/Ser8, ATM acts as a partner with ATR in the G2 phase checkpoint response, regulating key downstream events including Rad9, TopBP1 phosphorylation and KAP-1 phosphorylation/activation via the targeting of RPA32 Ser4/Ser8.
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