Abstract:
Setd8 regulates transcription elongation, mitotic DNA condensation, DNA damage response and replication licensing. Here we show that, in mitogen-stimulated liver-specific Setd8-KO mice, most of the hepatocytes are eliminated by necrosis but a significant number of them survive via entering a stage exhibiting several senescence-related features. Setd8-deficient hepatocytes had enlarged nuclei, chromosomal hyperploidy and nuclear engulfments progressing to the formation of intranuclear vesicles surrounded by nuclear lamina. These vesicles contain glycogen, cytoplasmic proteins and even entire organelles. We term this process \"endonucleosis\". Intranuclear vesicles are absent in hepatocytes of Setd8/Atg5 knockout mice, suggesting that the process requires the function of the canonical autophagy machinery. Endonucleosis and hyperploidization are temporary, early events in the surviving Setd8-deficient cells. Larger vesicles break down into microvesicles over time and are eventually eliminated. The results reveal sequential events in cells with extensive DNA damage, which function as part of survival mechanisms to prevent necrotic death.
摘要:
Settd8调节转录延伸,有丝分裂DNA凝聚,DNA损伤反应和复制许可。在这里我们展示,在丝裂原刺激的肝脏特异性Settd8-KO小鼠中,大多数肝细胞被坏死消除,但很大一部分通过进入表现出几种衰老相关特征的阶段而存活。Settd8缺陷肝细胞的细胞核增大,染色体超倍体和核吞噬发展为被核层包围的核内囊泡的形成。这些囊泡含有糖原,细胞质蛋白质甚至整个细胞器。我们称这个过程为“核酸内切症”。在Sed8/Atg5敲除小鼠的肝细胞中不存在核内囊泡,这表明该过程需要规范自噬机制的功能。内核症和超倍化是暂时的,存活的Settd8缺陷细胞中的早期事件。较大的囊泡随着时间的推移分解成微泡并最终被消除。结果揭示了广泛的DNA损伤细胞中的连续事件,作为防止坏死死亡的生存机制的一部分。