Over the course of DNA replication, DNA lesions, transcriptional intermediates and protein-DNA complexes can impair the progression of replication forks, thus resulting in replication stress. Failure to maintain replication fork integrity in response to replication stress leads to genomic instability and predisposes to the development of cancer and other genetic disorders. Multiple DNA damage and repair pathways have evolved to allow completion of DNA replication following replication stress, thus preserving genomic integrity. One of the processes commonly induced in response to replication stress is fork reversal, which consists in the remodeling of stalled replication forks into four-way DNA junctions. In normal conditions, fork reversal slows down replication fork progression to ensure accurate repair of DNA lesions and facilitates replication fork restart once the DNA lesions have been removed. However, in certain pathological situations, such as the deficiency of DNA repair factors that protect regressed forks from nuclease-mediated degradation, fork reversal can cause genomic instability. In this review, we describe the complex molecular mechanisms regulating fork reversal, with a focus on the role of the SNF2-family fork remodelers SMARCAL1, ZRANB3 and HLTF, and highlight the implications of fork reversal for tumorigenesis and cancer therapy.

在 DNA 复制过程中，DNA 损伤、转录中间体和蛋白质-DNA 复合物会损害复制叉的进程，从而导致复制压力。无法响应复制压力而保持复制叉的完整性会导致基因组不稳定并易患癌症和其他遗传疾病。多种 DNA 损伤和修复途径已经进化到允许在复制应激后完成 DNA 复制，从而保持基因组完整性。响应复制压力通常诱导的过程之一是叉反转，它包括将停滞的复制叉重塑为四向 DNA 连接。在正常情况下，叉逆转减慢复制叉的进展，以确保 DNA 损伤的准确修复，并在 DNA 损伤被去除后促进复制叉重新启动。然而，在某些病理情况下，例如保护回归叉免受核酸酶介导降解的 DNA 修复因子的缺乏，叉逆转会导致基因组不稳定。在这篇综述中，我们描述了调节叉逆转的复杂分子机制，重点是 SNF2 家族叉重塑 SMARCAL1、ZRANB3 和 HLTF 的作用，并强调了叉逆转对肿瘤发生和癌症治疗的影响。叉反转会导致基因组不稳定。在这篇综述中，我们描述了调节叉逆转的复杂分子机制，重点是 SNF2 家族叉重塑 SMARCAL1、ZRANB3 和 HLTF 的作用，并强调了叉逆转对肿瘤发生和癌症治疗的影响。叉反转会导致基因组不稳定。在这篇综述中，我们描述了调节叉逆转的复杂分子机制，重点是 SNF2 家族叉重塑 SMARCAL1、ZRANB3 和 HLTF 的作用，并强调了叉逆转对肿瘤发生和癌症治疗的影响。