Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Nat Commun. 2012;3:1000. doi: 10.1038/ncomms2008.
DNA damage as a result of environmental stress is recognized by sensor proteins that trigger repair mechanisms, or, if repair is unsuccessful, initiate apoptosis. Defects in DNA damage-induced apoptosis promote genomic instability and tumourigenesis. The protein ataxia-telangiectasia mutated (ATM) is activated by DNA double-strand breaks and regulates apoptosis via p53. Here we show that FOXO3 interacts with the ATM-Chk2-p53 complex, augments phosphorylation of the complex and induces the formation of nuclear foci in cells on DNA damage. FOXO3 is essential for DNA damage-induced apoptosis and conversely FOXO3 requires ATM, Chk2 and phosphorylated p53 isoforms to trigger apoptosis as a result of DNA damage. Under these conditions FOXO3 may also have a role in regulating chromatin retention of phosphorylated p53. These results suggest an essential link between FOXO3 and the ATM-Chk2-p53-mediated apoptotic programme following DNA damage.
由于环境压力导致的 DNA 损伤被传感器蛋白识别，这些蛋白会触发修复机制，或者如果修复不成功，则会启动细胞凋亡。DNA 损伤诱导的细胞凋亡缺陷会促进基因组不稳定和肿瘤发生。蛋白共济失调毛细血管扩张突变（ATM）被 DNA 双链断裂激活，并通过 p53 调节细胞凋亡。在这里，我们表明 FOXO3 与 ATM-Chk2-p53 复合物相互作用，增强复合物的磷酸化，并诱导细胞在 DNA 损伤时形成核焦点。FOXO3 对于 DNA 损伤诱导的细胞凋亡是必需的，相反，FOXO3 需要 ATM、Chk2 和磷酸化的 p53 同工型，才能在 DNA 损伤时引发细胞凋亡。在这些条件下，FOXO3 也可能在调节磷酸化 p53 的染色质保留方面发挥作用。这些结果表明，FOXO3 与 ATM-Chk2-p53 介导的凋亡程序之间存在着重要联系，这种联系是在 DNA 损伤之后产生的。
