Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242.
Department of Radiation Oncology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242.
Semin Cell Dev Biol. 2021 May;113:27-37. doi: 10.1016/j.semcdb.2020.10.001. Epub 2020 Oct 22.
DNA replication is laden with obstacles that slow, stall, collapse, and break DNA replication forks. At each obstacle, there is a decision to be made whether to bypass the lesion, repair or restart the damaged fork, or to protect stalled forks from further demise. Each "decision" draws upon multitude of proteins participating in various mechanisms that allow repair and restart of replication forks. Specific functions for many of these proteins have been described and an understanding of how they come together in supporting replication forks is starting to emerge. Many questions, however, remain regarding selection of the mechanisms that enable faithful genome duplication and how "normal" intermediates in these mechanisms are sometimes funneled into "rogue" processes that destabilize the genome and lead to cancer, cell death, and emergence of chemotherapeutic resistance. In this review we will discuss molecular mechanisms of DNA damage bypass and replication fork protection and repair. We will specifically focus on the key players that define which mechanism is employed including: PCNA and its control by posttranslational modifications, translesion synthesis DNA polymerases, molecular motors that catalyze reversal of stalled replication forks, proteins that antagonize fork reversal and protect reversed forks from nucleolytic degradation, and the machinery of homologous recombination that helps to reestablish broken forks. We will also discuss risks to genome integrity inherent in each of these mechanisms.
DNA 复制过程中充满了各种障碍，这些障碍会减缓、停滞、崩溃和断裂 DNA 复制叉。在每个障碍处，都需要做出决定是绕过损伤、修复或重新启动受损的叉、还是保护停滞的叉免受进一步破坏。每个“决定”都依赖于多种参与各种机制的蛋白质，这些机制允许修复和重新启动复制叉。许多这些蛋白质的特定功能已经被描述出来，并且它们如何协同作用以支持复制叉的机制开始显现出来。然而，仍有许多问题涉及到选择能够实现忠实基因组复制的机制，以及这些机制中的“正常”中间体如何有时会被引导到“异常”过程中，这些过程会破坏基因组并导致癌症、细胞死亡和化疗耐药性的出现。在这篇综述中，我们将讨论 DNA 损伤绕过和复制叉保护和修复的分子机制。我们将特别关注定义采用哪种机制的关键因素，包括：PCNA 及其翻译后修饰的控制、跨损伤合成 DNA 聚合酶、催化停滞复制叉反转的分子马达、拮抗叉反转并保护反转叉免受核酸酶降解的蛋白质，以及有助于重新建立断裂叉的同源重组机制。我们还将讨论这些机制中固有的基因组完整性风险。
