LSU Health Shreveport, Department of Pathology, Shreveport, LA, United States.
Department of Pathology & Translational Pathobiology, Louisiana State University Health Sciences Center, Shreveport, LA, 71130, United States.
Redox Biol. 2021 Jan;38:101675. doi: 10.1016/j.redox.2020.101675. Epub 2020 Oct 28.
Recent evidence has revealed that exposing cells to exogenous H 2 S or inhibiting cellular H 2 S synthesis can modulate cell cycle checkpoints, DNA damage and repair, and the expression of proteins involved in the maintenance of genomic stability, all suggesting that H 2 S plays an important role in the DNA damage response (DDR). Here we review the role of H 2 S in the DRR and maintenance of genomic stability. Treatment of various cell types with pharmacologic H 2 S donors or cellular H 2 S synthesis inhibitors modulate the G 1 checkpoint, inhibition of DNA synthesis, and cause p21, and p53 induction. Moreover, in some cell models H 2 S exposure induces PARP-1 and g-H2AX foci formation, increases PCNA, CHK2, Ku70, Ku80, and DNA polymerase-d protein expression, and maintains mitochondrial genomic stability. Our group has also revealed that H 2 S bioavailability and the ATR kinase regulate each other with ATR inhibition lowering cellular H 2 S concentrations, whereas intracellular H 2 S concentrations regulate ATR kinase activity via ATR serine 435 phosphorylation. In summary, these findings have many implications for the DDR, for cancer chemotherapy, and fundamental biochemical metabolic pathways involving H 2 S.
最近的证据表明，将细胞暴露于外源性 H₂S 或抑制细胞内 H₂S 的合成可以调节细胞周期检查点、DNA 损伤和修复，以及参与维持基因组稳定性的蛋白质的表达，这表明 H₂S 在 DNA 损伤反应（DDR）中发挥着重要作用。在这里，我们综述了 H₂S 在 DDR 和基因组稳定性维持中的作用。用药理学 H₂S 供体或细胞内 H₂S 合成抑制剂处理各种细胞类型可以调节 G1 检查点、抑制 DNA 合成，并诱导 p21 和 p53 的表达。此外，在一些细胞模型中，H₂S 的暴露会诱导 PARP-1 和 g-H2AX 焦点的形成，增加 PCNA、CHK2、Ku70、Ku80 和 DNA 聚合酶-d 蛋白的表达，并维持线粒体基因组的稳定性。我们的研究小组还揭示了 H₂S 的生物利用度和 ATR 激酶之间的相互调节，ATR 抑制降低了细胞内 H₂S 的浓度，而细胞内 H₂S 浓度通过 ATR 丝氨酸 435 的磷酸化调节 ATR 激酶的活性。总之，这些发现对 DDR、癌症化疗以及涉及 H₂S 的基本生化代谢途径都具有重要意义。
