Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada.
Essays Biochem. 2020 Oct 26;64(5):753-764. doi: 10.1042/EBC20200016.
Healthy cells experience thousands of DNA lesions per day during normal cellular metabolism, and ionizing radiation and chemotherapeutic drugs rely on DNA damage to kill cancer cells. In response to such lesions, the DNA damage response (DDR) activates cell-cycle checkpoints, initiates DNA repair mechanisms, or promotes the clearance of irreparable cells. Work over the past decade has revealed broader influences of the DDR, involving inflammatory gene expression following unresolved DNA damage, and immune surveillance of damaged or mutated cells. Subcellular structures called micronuclei, containing broken fragments of DNA or whole chromosomes that have been isolated away from the rest of the genome, are now recognized as one mediator of DDR-associated immune recognition. Micronuclei can initiate pro-inflammatory signaling cascades, or massively degrade to invoke distinct forms of genomic instability. In this mini-review, we aim to provide an overview of the current evidence linking the DDR to activation of the immune response through micronuclei formation, identifying key areas of interest, open questions, and emerging implications.
健康细胞在正常细胞代谢过程中每天会经历数千个 DNA 损伤，电离辐射和化疗药物依赖于 DNA 损伤来杀死癌细胞。为了应对这些损伤，DNA 损伤反应 (DDR) 会激活细胞周期检查点，启动 DNA 修复机制，或促进无法修复的细胞清除。过去十年的工作揭示了 DDR 的更广泛影响，包括未解决的 DNA 损伤后炎症基因的表达，以及对受损或突变细胞的免疫监视。现在，被称为微核的亚细胞结构被认为是 DDR 相关免疫识别的一种介质，其中包含与基因组其余部分隔离的 DNA 断裂片段或整条染色体。微核可以引发促炎信号级联反应，或者大量降解以引发不同形式的基因组不稳定性。在这篇迷你综述中，我们旨在概述 DDR 通过微核形成与免疫反应激活之间的联系的现有证据，确定关键的研究领域、未解决的问题和新兴的影响。
