Filamentous actin (F-actin) provides cells with mechanical support and promotes the mobility of intracellular structures. Although F-actin is traditionally considered to be cytoplasmic, here we reveal that nuclear F-actin participates in the replication stress response. Using live and super-resolution imaging, we find that nuclear F-actin is polymerized in response to replication stress through a pathway regulated by ATR-dependent activation of mTORC1, and nucleation through IQGAP1, WASP and ARP2/3. During replication stress, nuclear F-actin increases the nuclear volume and sphericity to counteract nuclear deformation. Furthermore, F-actin and myosin II promote the mobility of stressed-replication foci to the nuclear periphery through increasingly diffusive motion and directed movements along the nuclear actin filaments. These actin functions promote replication stress repair and suppress chromosome and mitotic abnormalities. Moreover, we find that nuclear F-actin is polymerized in vivo in xenograft tumours after treatment with replication-stress-inducing chemotherapeutic agents, indicating that this pathway has a role in human disease.

丝状肌动蛋白 (F-actin) 为细胞提供机械支持并促进细胞内结构的移动性。虽然 F-肌动蛋白传统上被认为是细胞质的，但在这里我们揭示了核 F-肌动蛋白参与复制应激反应。使用实时和超分辨率成像，我们发现核 F-肌动蛋白通过受 ATR 依赖性激活 mTORC1 调节的途径以及通过 IQGAP1、WASP 和 ARP2/3 的成核来响应复制压力而聚合。在复制应力期间，核 F-肌动蛋白增加核体积和球形度以抵消核变形。此外，F-肌动蛋白和肌球蛋白 II 通过越来越多的扩散运动和沿着核肌动蛋白丝的定向运动促进应力复制灶向核外围的移动。这些肌动蛋白功能促进复制应激修复并抑制染色体和有丝分裂异常。此外，我们发现在用诱导复制应激的化学治疗剂治疗后，核 F-肌动蛋白在异种移植肿瘤中体内聚合，表明该途径在人类疾病中起作用。