Yang Xiaohong H, Shiotani Bunsyo, Classon Marie, Zou Lee
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Genes Dev. 2008 May 1;22(9):1147-52. doi: 10.1101/gad.1632808.
Chk1 is a kinase crucial for genomic integrity and an effector of ATR (ATM and Rad3-related) in DNA damage response. Here, we show that Chk1 regulates the DNA damage-induced ubiquitination of proliferating cell nuclear antigen (PCNA), which facilitates the continuous replication of damaged DNA. Surprisingly, this Chk1 function requires the DNA replication protein Claspin but not ATR. Claspin, which is stabilized by Chk1, regulates the binding of the ubiquitin ligase Rad18 to chromatin. Timeless, a Claspin-associating protein, is also required for efficient PCNA ubiquitination. Thus, Chk1 and the Claspin-Timeless module of replication forks not only participate in ATR signaling, but also protect stressed forks independently of ATR.
Chk1是一种对基因组完整性至关重要的激酶，是DNA损伤应答中ATR（ATM和Rad3相关蛋白）的效应器。在此，我们表明Chk1调节DNA损伤诱导的增殖细胞核抗原（PCNA）的泛素化，这有助于受损DNA的持续复制。令人惊讶的是，这种Chk1功能需要DNA复制蛋白Claspin而不是ATR。由Chk1稳定的Claspin调节泛素连接酶Rad18与染色质的结合。高效的PCNA泛素化也需要与Claspin相关的蛋白Timeless。因此，Chk1和复制叉的Claspin-Timeless模块不仅参与ATR信号传导，而且独立于ATR保护应激的复制叉。
