Public Health Research Institute and Department of Microbiology, Biochemistry & Molecular Genetics, New Jersey Medical School, Rutgers University, 225 Warren Street, Newark, NJ, 07103, USA.
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, South Xiang-An Road, Xiang-An District, Xiamen, Fujian Province, 361102, China.
Nat Microbiol. 2017 Dec;2(12):1667-1675. doi: 10.1038/s41564-017-0037-y. Epub 2017 Oct 2.
Nutrient starvation usually halts cell growth rather than causing death. Thymine starvation is exceptional, because it kills cells rapidly. This phenomenon, called thymineless death (TLD), underlies the action of several antibacterial, antimalarial, anticancer, and immunomodulatory agents. Many explanations for TLD have been advanced, with recent efforts focused on recombination proteins and replication origin (oriC) degradation. Because current proposals account for only part of TLD and because reactive oxygen species (ROS) are implicated in bacterial death due to other forms of harsh stress, we investigated the possible involvement of ROS in TLD. Here, we show that thymine starvation leads to accumulation of both single-stranded DNA regions and intracellular ROS, and interference with either event protects bacteria from double-stranded DNA breakage and TLD. Elevated levels of single-stranded DNA were necessary but insufficient for TLD, whereas reduction of ROS to background levels largely abolished TLD. We conclude that ROS contribute to TLD by converting single-stranded DNA lesions into double-stranded DNA breaks. Participation of ROS in the terminal phases of TLD provides a specific example of how ROS contribute to stress-mediated bacterial self-destruction.
营养饥饿通常会停止细胞生长，而不是导致细胞死亡。胸腺嘧啶饥饿是例外，因为它会迅速杀死细胞。这种现象称为无胸腺嘧啶死亡（TLD），它是几种抗菌、抗疟、抗癌和免疫调节药物的作用基础。已经提出了许多关于 TLD 的解释，最近的研究重点是重组蛋白和复制起点（oriC）的降解。由于目前的提议仅解释了 TLD 的一部分，并且由于活性氧物种（ROS）与其他形式的恶劣应激导致的细菌死亡有关，因此我们研究了 ROS 是否可能参与 TLD。在这里，我们表明胸腺嘧啶饥饿会导致单链 DNA 区域和细胞内 ROS 的积累，并且干扰这两种情况都可以保护细菌免受双链 DNA 断裂和 TLD 的侵害。单链 DNA 的积累是必需的，但不足以引起 TLD，而将 ROS 降低到背景水平则在很大程度上消除了 TLD。我们的结论是，ROS 通过将单链 DNA 损伤转化为双链 DNA 断裂来促进 TLD。ROS 参与 TLD 的终末阶段为 ROS 如何促进应激介导的细菌自我毁灭提供了一个具体的例子。
