Institute of Radioisotopes and Radiodiagnostic Products, National Centre for Scientific Research "Demokritos", 15310 Ag. Paraskevi Attikis, Athens, Greece.
Mutat Res. 2011 Jun 3;711(1-2):174-86. doi: 10.1016/j.mrfmmm.2010.12.011. Epub 2010 Dec 24.
The formation of diverse chromosomal aberrations following irradiation and the variability in radiosensitivity at different cell-cycle stages remain a long standing controversy, probably because most of the studies have focused on elucidating the enzymatic mechanisms involved using simple DNA substrates. Yet, recognition, processing and repair of DNA damage occur within the nucleoprotein complex of chromatin which is dynamic in nature, capable of rapid unfolding, disassembling, assembling and refolding. The present work reviews experimental work designed to investigate the impact of chromatin dynamics and chromosome conformation changes during cell-cycle in the formation of chromosomal aberrations. Using conventional cytogenetics and premature chromosome condensation to visualize interphase chromatin, the data presented support the hypothesis that chromatin dynamic changes during cell-cycle are important determinants in the conversion of sub-microscopic DNA lesions into chromatid breaks. Consequently, the type and yield of radiation-induced chromosomal aberrations at a given cell-cycle-stage depends on the combined effect of DNA repair processes and chromatin dynamics, which is cell-cycle-regulated and subject to up- or down-regulation following radiation exposure or genetic alterations. This new hypothesis is used to explain the variability in radiosensitivity observed at various cell-cycle-stages, among mutant cells and cells of different origin, or among different individuals, and to revisit unresolved issues and unanswered questions. In addition, it is used to better understand hypersensitivity of AT cells and to provide an improved predictive G2-assay for evaluating radiosensitivity at individual level. Finally, experimental data at single cell level obtained using hybrid cells suggest that the proposed hypothesis applies only to the irradiated component of the hybrid.
照射后形成多种染色体畸变和不同细胞周期阶段的放射敏感性变化一直存在争议，这可能是因为大多数研究都集中在使用简单的 DNA 底物阐明涉及的酶促机制上。然而，DNA 损伤的识别、加工和修复发生在染色质的核蛋白复合物内，该复合物本质上是动态的，能够快速展开、解体、组装和重折叠。本研究综述了旨在研究细胞周期中染色质动力学和染色体构象变化对染色体畸变形成影响的实验工作。通过常规细胞遗传学和早熟染色体凝聚来可视化间期染色质，所提供的数据支持了这样一种假设，即在细胞周期中染色质动力学变化是将亚微观 DNA 损伤转化为染色单体断裂的重要决定因素。因此，给定细胞周期阶段的辐射诱导染色体畸变的类型和产量取决于 DNA 修复过程和染色质动力学的综合效应，该效应受细胞周期调控，并在辐射暴露或遗传改变后上调或下调。这一新假设用于解释在不同细胞周期阶段、突变细胞和不同来源的细胞或不同个体中观察到的放射敏感性变化，并重新审视未解决的问题和未回答的问题。此外，它还用于更好地理解 AT 细胞的超敏感性，并提供一种改进的预测 G2 测定法，以评估个体水平的放射敏感性。最后，使用杂交细胞在单细胞水平获得的实验数据表明，所提出的假设仅适用于杂交细胞的照射部分。
