Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
Mol Oncol. 2019 Feb;13(2):307-321. doi: 10.1002/1878-0261.12403. Epub 2018 Dec 3.
The ATR/CHK1 pathway is a key effector of cellular response to DNA damage and therefore is a critical regulator of genomic stability. While the ATR/CHK1 pathway is often inactivated by mutations, CHK1 itself is rarely mutated in human cancers. Thus, cellular levels of CHK1 likely play a key role in the maintenance of genomic stability and preventing tumorigenesis. Glucose deprivation is observed in many solid tumors due to high glycolytic rates of cancer cells and insufficient vascularization, yet cancer cells have devised mechanisms to survive in conditions of low glucose. Although CHK1 degradation through the ubiquitin-proteasome pathway following glucose deprivation has been previously reported, the detailed molecular mechanisms remain elusive. Here, we show that CHK1 is ubiquitinated and degraded upon glucose deprivation by the Skp1-Cullin-F-box (β-TrCP) E3 ubiquitin ligase. Specifically, CHK1 contains a β-TrCP recognizable degron domain, which is phosphorylated by AMPK in response to glucose deprivation, allowing for β-TrCP to recognize CHK1 for subsequent ubiquitination and degradation. Our results provide a novel mechanism by which glucose metabolism regulates a DNA damage effector, and imply that glucose deprivation, which is often found in solid tumor microenvironments, may enhance mutagenesis, clonal expansion, and tumor progression by triggering CHK1 degradation.
ATR/CHK1 通路是细胞对 DNA 损伤反应的关键效应因子，因此是基因组稳定性的关键调节剂。虽然 ATR/CHK1 通路通常因突变而失活，但 CHK1 本身在人类癌症中很少发生突变。因此，CHK1 的细胞水平可能在维持基因组稳定性和防止肿瘤发生方面发挥关键作用。由于癌细胞的高糖酵解率和血管生成不足，许多实体瘤中都会出现葡萄糖剥夺，但癌细胞已经设计出在低糖条件下存活的机制。尽管先前已经报道了葡萄糖剥夺后通过泛素蛋白酶体途径降解 CHK1，但详细的分子机制仍不清楚。在这里，我们表明葡萄糖剥夺后，Skp1-Cullin-F-box（β-TrCP）E3 泛素连接酶使 CHK1 发生泛素化和降解。具体而言，CHK1 含有一个可被 β-TrCP 识别的降解结构域，该结构域在葡萄糖剥夺时被 AMPK 磷酸化，从而允许 β-TrCP 识别 CHK1 进行随后的泛素化和降解。我们的结果提供了一种新的机制，即葡萄糖代谢调节 DNA 损伤效应因子，并且暗示在实体瘤微环境中经常发现的葡萄糖剥夺可能通过触发 CHK1 降解来增强突变、克隆扩增和肿瘤进展。
