Department of Biological Sciences, Tata Institute of Fundamental Research, Colaba, Mumbai 400005, India.
Department of Biological Sciences, Tata Institute of Fundamental Research, Colaba, Mumbai 400005, India
J Cell Sci. 2017 Sep 15;130(18):2984-2995. doi: 10.1242/jcs.200782. Epub 2017 Jul 27.
The phosphorylation of the variant histone H2Ax (denoted γH2Ax; γH2Av in flies) constitutes an important signalling event in DNA damage sensing, ensuring effective repair by recruiting DNA repair machinery. In contrast, the γH2Av response has also been reported in dying cells, where it requires activation of caspase-activated DNases (CADs). Moreover, caspases are known to be required downstream of DNA damage for cell death execution. We show here, for the first time, that the initiator caspase Dronc acts as an upstream regulator of the DNA damage response (DDR) independently of executioner caspases by facilitating γH2Av signalling, possibly through a function that is not related to apoptosis. Such a γH2Av response is mediated by ATM rather than ATR, suggesting that Dronc function is required upstream of ATM. In contrast, the role of γH2Av in cell death requires effector caspases and is associated with fragmented nuclei. Our study uncovers a novel function of Dronc in response to DNA damage aimed at promoting DDR via γH2Av signalling in intact nuclei. We propose that Dronc plays a dual role that can either initiate DDR or apoptosis depending upon its level and the required threshold of its activation in damaged cells.This article has an associated First Person interview with the first author of the paper.
变体组蛋白 H2Ax 的磷酸化（表示为 γH2Ax；在果蝇中为γH2Av）是 DNA 损伤感应中的一个重要信号事件，通过招募 DNA 修复机制来确保有效的修复。相比之下，γH2Av 反应也在垂死的细胞中被报道过，在垂死的细胞中，它需要激活半胱氨酸天冬氨酸蛋白酶激活的 DNA 酶（CADs）。此外，众所周知，细胞凋亡下游的半胱氨酸天冬氨酸蛋白酶对于细胞死亡的执行是必需的。我们在这里首次表明，起始半胱氨酸天冬氨酸蛋白酶 Dronc 通过促进 γH2Av 信号传导，作为 DNA 损伤反应（DDR）的上游调节剂，而不依赖于执行半胱氨酸天冬氨酸蛋白酶，这可能是通过与其凋亡无关的功能。这种 γH2Av 反应是由 ATM 介导的，而不是 ATR 介导的，这表明 Dronc 的功能是在 ATM 的上游所必需的。相比之下，γH2Av 在细胞死亡中的作用需要效应半胱氨酸天冬氨酸蛋白酶，并且与核碎裂有关。我们的研究揭示了 Dronc 在应对 DNA 损伤中的一个新功能，即通过 γH2Av 信号传导促进 DDR，而这种功能是在完整的核中发挥的。我们提出 Dronc 具有双重作用，根据其在受损细胞中的水平和激活所需的阈值，它可以启动 DDR 或细胞凋亡。本文附有该论文第一作者的第一人称访谈。
