State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.
Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism & Integrative Biology, Fudan University, Shanghai, China.
J Cell Physiol. 2022 Nov;237(11):4169-4179. doi: 10.1002/jcp.30861. Epub 2022 Aug 22.
Poly(ADP-ribose) polymerase 1 (PARP1) plays a key role in genome stability by modulating DNA-damage responses. Activated by DNA interruptions through ultraviolet (UV) exposure, PARylation is synthesized by PARP1 and serves as a survival mechanism for cancer and metabolic diseases. Several strategies including ROS and antimicrobial peptides (AMPs) function in host defenses, while the targeted tissue and mechanism under DNA damage are unknown. Here, we show that DNA damage induces responses specifically in the gut tissue. The knockdown of PARP1 reduces the activation of PARylation. Parp1 knockdown under DNA damage results in over-accumulated ROS and secretion of AMPs through the regulation of Relish, a subunit of nuclear factor-κB (NF-κB). Double-knockdown of Parp1 and Relish specifically in the gut inhibits AMP secretion. In conclusion, the host defense is achieved through ROS accumulation rather than the AMPs under DNA damage. In contrast, the knockdown of PARP1 exacerbates ROS accumulation to a harmful level. Under this circumstance, NF-κb targeted AMP secretion is provoked for host defense. Microbiome and functional analysis provide evidence for the hazard of DNA damage and show variations in the metabolic pathways following Parp1 inhibition. Our findings suggest the notion that PARP1 inhibition contributes to ROS accumulation under DNA damage and its role in NF-κb activation for host defense.
聚（ADP-核糖）聚合酶 1（PARP1）通过调节 DNA 损伤反应在基因组稳定性中发挥关键作用。PARP1 通过紫外线（UV）暴露中断 DNA 激活，合成 PAR 化，作为癌症和代谢疾病的生存机制。几种策略包括活性氧（ROS）和抗菌肽（AMPs）在宿主防御中发挥作用，而在 DNA 损伤下靶向组织和机制尚不清楚。在这里，我们表明 DNA 损伤会在肠道组织中引起特定的反应。PARP1 的敲低会减少 PAR 化的激活。DNA 损伤下的 Parp1 敲低会导致 ROS 的过度积累，并通过核因子-κB（NF-κB）的一个亚基 Relish 调节 AMP 的分泌。肠道中 Parp1 和 Relish 的双敲低会抑制 AMP 的分泌。总之，宿主防御是通过 ROS 积累而不是 DNA 损伤下的 AMPs 实现的。相反，PARP1 的敲低会将 ROS 积累加剧到有害水平。在这种情况下，NF-κB 靶向 AMP 的分泌是为了宿主防御。微生物组和功能分析为 DNA 损伤的危害提供了证据，并显示了 Parp1 抑制后代谢途径的变化。我们的研究结果表明，PARP1 抑制会导致 DNA 损伤下的 ROS 积累，以及其在 NF-κB 激活中的作用，以实现宿主防御。
