CaMKK2 and CHK1 phosphorylate human STN1 in response to replication stress to protect stalled forks from aberrant resection.
CaMKK2 and CHK1 phosphorylate human STN1 in response to replication stress to protect stalled forks from aberrant resection.
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DOI：
10.1038/s41467-023-43685-2
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发表时间：
2023-11-30
影响因子：
16.6
通讯作者：
Chai, Weihang
中科院分区：
文献类型：
--
作者：
Jaiswal, Rishi Kumar;Lei, Kai-Hang;Chastain, Megan;Wang, Yuan;Shiva, Olga;Li, Shan;You, Zhongsheng;Chi, Peter;Chai, Weihang
保持复制叉稳定对于保护基因组完整性至关重要;因此，其保护受到高度监管。CTC 1-STN 1-TEN 1（CST）复合物保护停滞的叉免于异常MRE 11介导的新生链DNA降解（NSD）。然而，CST在分叉处的激活机制尚不清楚。在这里，我们报告说，STN 1磷酸化的内在无序区域。STN 1磷酸化的丧失减少了复制应激诱导的STN 1定位于停滞的叉，提高了NSD，增加了MRE 11接近停滞的叉，并减少了RAD 51在叉的定位，导致在扰动的DNA复制条件下增加的基因组不稳定性。STN 1被ATR-CHK 1和钙敏感激酶CaMKK 2磷酸化，以响应羟基脲/阿非迪霉素处理或升高的细胞溶质钙浓度。癌症相关的STN 1变体损害STN 1磷酸化，赋予叉保护的无能。总的来说，我们的研究揭示了CaMKK 2和ATR-CHK 1靶向STN 1以实现其叉保护功能，并表明STN 1磷酸化在癌症发展中的重要作用。在这里，作者表明钙敏感激酶CaMKK 2磷酸化STN 1以响应复制应激和升高的细胞溶质钙浓度，以保护停滞的复制叉免于异常的MRE 11降解。癌症相关的STN 1突变破坏STN 1磷酸化，导致叉不稳定。
Keeping replication fork stable is essential for safeguarding genome integrity; hence, its protection is highly regulated. The CTC1-STN1-TEN1 (CST) complex protects stalled forks from aberrant MRE11-mediated nascent strand DNA degradation (NSD). However, the activation mechanism for CST at forks is unknown. Here, we report that STN1 is phosphorylated in its intrinsic disordered region. Loss of STN1 phosphorylation reduces the replication stress-induced STN1 localization to stalled forks, elevates NSD, increases MRE11 access to stalled forks, and decreases RAD51 localization at forks, leading to increased genome instability under perturbed DNA replication condition. STN1 is phosphorylated by both the ATR-CHK1 and the calcium-sensing kinase CaMKK2 in response to hydroxyurea/aphidicolin treatment or elevated cytosolic calcium concentration. Cancer-associated STN1 variants impair STN1 phosphorylation, conferring inability of fork protection. Collectively, our study uncovers that CaMKK2 and ATR-CHK1 target STN1 to enable its fork protective function, and suggests an important role of STN1 phosphorylation in cancer development. Here the authors show that the calcium-sensing kinase CaMKK2 phosphorylates STN1 in response to replication stress and elevated cytosolic calcium concentration to protect stalled replication forks from aberrant MRE11 degradation. Cancer-associated STN1 mutations abolish STN1 phosphorylation, resulting in fork instability.
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