School of Life Sciences, The Engineering Research Center of Sustainable Development and Utilization of Biomass Energy, Yunnan Normal University, Kunming, Yunnan 650500, China.
Department of Food Safety, Institute of Nutrition and Food Sciences, University of Bonn, Germany.
Mutat Res Rev Mutat Res. 2022 Jul-Dec;790:108440. doi: 10.1016/j.mrrev.2022.108440. Epub 2022 Aug 12.
In higher eukaryotes, sophisticate regulation of genome function requires all chromosomes to be packed into a single nucleus. Micronucleus (MN), the dissociative nucleus-like structure frequently observed in aging and multiple disease settings, has critical, yet under-recognized, pathophysiological functions. Micronuclei (MNi) have recently emerged as major sources of cytosolic DNA that can activate the cGAS-STING axis in a cell-intrinsic manner. However, MNi induced from different genotoxic stressors display great heterogeneity in binding or activating cGAS and the signaling responses downstream of the MN-induced cGAS-STING axis have divergent outcomes including autoimmunity, autoinflammation, metastasis, or cell death. Thus, full characterization of molecular network underpinning the interplay of cGAS and MN is important to elucidate the pathophysiological roles of immunogenic MN and design improved drugs that selectively target cancer via boosting the MN-derived cGAS-STING axis. Here, we summarize our current understanding of the mechanisms for self-DNA discrimination by cGAS. We focus on discussing how MN immunogencity is dictated by multiple mechanisms including integrity of micronuclear envelope, state of nucleosome and DNA, competitive factors, damaged mitochondrial DNA and micronucleophagy. We also describe emerging links between immunogenic MN and human diseases including cancer, neurodegenerative diseases and COVID-19. Particularly, we explore the exciting concept of inducing immunogenic MN as a therapeutic approach in treating cancer. We propose a new theoretical framework to describe immunogenic MN as a biological sensor to modulate cellular processes in response to genotoxic stress and provide perspectives on developing novel experimental approaches to unravel the complexity of MN immunogenicity regulation and immunogenic MN pathophysiology.
在高等真核生物中，基因组功能的复杂调节需要将所有染色体包装到一个单个核中。微核（MN）是衰老和多种疾病状态中经常观察到的分离核样结构，具有关键但尚未被充分认识的病理生理功能。微核（MNi）最近已成为细胞质 DNA 的主要来源，可以以细胞内在的方式激活 cGAS-STING 轴。然而，来自不同遗传毒性应激源的 MNi 在结合或激活 cGAS 方面表现出很大的异质性，并且 MN 诱导的 cGAS-STING 轴下游的信号反应具有不同的结果，包括自身免疫、自身炎症、转移或细胞死亡。因此，充分表征 cGAS 和 MN 相互作用的分子网络对于阐明免疫原性 MN 的病理生理作用以及设计通过增强 MN 衍生的 cGAS-STING 轴来选择性靶向癌症的改良药物非常重要。在这里，我们总结了我们目前对 cGAS 识别自身 DNA 的机制的理解。我们专注于讨论 MN 免疫原性如何由多种机制决定，包括微核包膜的完整性、核小体和 DNA 的状态、竞争因素、受损的线粒体 DNA 和微核吞噬。我们还描述了免疫原性 MN 与人类疾病之间的新兴联系，包括癌症、神经退行性疾病和 COVID-19。特别是，我们探讨了诱导免疫原性 MN 作为治疗癌症的治疗方法的令人兴奋的概念。我们提出了一个新的理论框架来描述免疫原性 MN 作为生物传感器，以响应遗传毒性应激来调节细胞过程，并提供了关于开发新的实验方法来揭示 MN 免疫原性调节和免疫原性 MN 病理生理学复杂性的观点。
