Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
Nucleic Acids Res. 2021 Jul 21;49(13):7224-7238. doi: 10.1093/nar/gkab344.
A universal response to replication stress is replication fork reversal, where the nascent complementary DNA strands are annealed to form a protective four-way junction allowing forks to avert DNA damage while replication stress is resolved. However, reversed forks are in turn susceptible to nucleolytic digestion of the regressed nascent DNA arms and rely on dedicated mechanisms to protect their integrity. The most well studied fork protection mechanism involves the BRCA pathway and its ability to catalyze RAD51 nucleofilament formation on the reversed arms of stalled replication forks. Importantly, the inability to prevent the degradation of reversed forks has emerged as a hallmark of BRCA deficiency and underlies genome instability and chemosensitivity in BRCA-deficient cells. In the past decade, multiple factors underlying fork stability have been discovered. These factors either cooperate with the BRCA pathway, operate independently from it to augment fork stability in its absence, or act as enablers of fork degradation. In this review, we examine these novel determinants of fork stability, explore the emergent conceptual underpinnings underlying fork protection, as well as the impact of fork protection on cellular viability and cancer therapy.
普遍的复制应激反应是复制叉反转，此时新合成的互补 DNA 链退火形成保护性四链结，允许叉在复制应激得到解决的同时避免 DNA 损伤。然而，反转的叉反过来容易受到回归新生 DNA 臂的核酶消化，并且依赖于专门的机制来保护其完整性。研究最充分的叉保护机制涉及 BRCA 途径及其在停滞复制叉反转臂上催化 RAD51 核丝形成的能力。重要的是，无法防止反转叉的降解已成为 BRCA 缺陷的标志，并构成了 BRCA 缺陷细胞中的基因组不稳定性和化疗敏感性的基础。在过去的十年中，已经发现了多种维持叉稳定性的因素。这些因素要么与 BRCA 途径合作，要么在其缺失时独立于其运作以增强叉的稳定性，要么作为叉降解的促进剂。在这篇综述中，我们检查了这些新的叉稳定性决定因素，探讨了叉保护的新兴概念基础，以及叉保护对细胞活力和癌症治疗的影响。
