Micronuclei as biomarkers of DNA damage, aneuploidy, inducers of chromosomal hypermutation and as sources of pro-in fl ammatory DNA in humans
Micronuclei as biomarkers of DNA damage, aneuploidy, inducers of chromosomal hypermutation and as sources of pro-in fl ammatory DNA in humans
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DOI：
10.1016/j.mrrev.2020.108342
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发表时间：
2020-10-01
影响因子：
5.3
通讯作者：
Kirsch-Volders, Micheline
中科院分区：
文献类型：
--
作者：
Fenech, Michael;Knasmueller, Siegfried;Kirsch-Volders, Micheline
微核（MNi）是人类DNA损伤和染色体不稳定性的最广泛研究的生物标志物之一。它们起源于有丝分裂过程中不包含在子核中的染色体片段或完整染色体。其形成的主要原因是染色体片段或整个染色体中缺乏功能性着丝粒，或者有丝分裂系统的一种或多种蛋白质中存在缺陷，因此不能正确分离染色体。已经开发了测定法来测量外周血淋巴细胞、红细胞以及各种类型的上皮细胞如颊、鼻、尿路上皮和宫颈细胞中的MNi。其中一些试验已进一步开发为微核（MN）细胞组试验，以包括其他核异常、细胞死亡和核分裂生物标志物。此外，分子探针的使用已被广泛采用，以了解MNi的机制起源。人体MN试验用于研究不良环境、生活方式和职业因素的遗传毒性效应、DNA损伤的遗传易感性，以及确定加速衰老和受基因组不稳定性影响的疾病（如发育缺陷和癌症）的风险。新兴的新知识表明，被困在MNi中的染色体可以经历高速率的片段化并变得大规模重排，这突出了MN形成不仅是诱导DNA损伤的生物标志物，而且是驱动超突变的机制的可能性。此外，最近的另一项研究表明，从破坏的MNi中泄漏的DNA和染色质触发了先天免疫cGAS-STING机制，该机制促进炎症，如果不解决，可能导致广泛的年龄相关疾病。由于这些原因，人类的MN检测已成为所有生命阶段疾病发生和进展的日益重要的生物标志物。(C)2020爱思唯尔B. V.保留所有权利。
Micronuclei (MNi) are among the most widely studied biomarkers of DNA damage and chromosomal instability in humans. They originate from chromosome fragments or intact chromosomes that are not included in daughter nuclei during mitosis. The main reasons for their formation are a lack of functional centromere in the chromosome fragments or whole chromosomes or defects in one or more of the proteins of the mitotic system that, consequently, fails to segregate chromosomes properly. Assays have been developed to measure MNi in peripheral blood lymphocytes, red blood cells as well as various types of epithelial cells such as buccal, nasal, urothelial and cervical cells. Some of the assays have been further developed into micronucleus (MN) cytome assays to include additional nuclear anomalies, cell death and nuclear division biomarkers. In addition, the use of molecular probes has been adopted widely for the purpose of understanding the mechanistic origin of MNi. MN assays in humans are used for the purpose of investigating the genotoxic effects of adverse environmental, life-style and occupational factors, genetic susceptibility to DNA damage, and for determining risk of accelerated aging and diseases affected by genomic instability such as developmental defects and cancer. The emerging new knowledge showing that chromosomes trapped in MNi can undergo a high rate of fragmentation and become massively rearranged have highlighted the possibility that MN formation is not only a biomarker of induced DNA damage but also a mechanism that drives hypermutation. Furthermore, another line of recent research showed that DNA and chromatin leaking from disrupted MNi triggers the innate immune cGAS-STING mechanism that promotes inflammation which can cause a wide-range of age-related diseases if left unresolved. For these reasons, MN assays in humans have become an increasingly important biomarker of disease initiation and progression across all life-stages. (C) 2020 Elsevier B.V. All rights reserved.