Nuclear myosin VI maintains replication fork stability

The actin cytoskeleton is of fundamental importance for cellular structure and plasticity. However, abundance and function of filamentous (F-) actin in the nucleus are still controversial. Here we show that the actin-based molecular motor myosin VI contributes to the stabilization of stalled or reversed replication forks. In response to DNA replication stress, myosin VI associates with stalled replication intermediates and cooperates with the AAA ATPase WRNIP1 in protecting these structures from DNA2-mediated nucleolytic attack. Using functionalized DARPins to manipulate myosin VI levels in a compartment-specific manner, we provide evidence for the direct involvement of myosin VI in the nucleus and against a contribution of the abundant cytoplasmic pool during the replication stress response.

肌动蛋白细胞骨架（actin cytoskeleton）对细胞结构与可塑性具有基础性重要意义。然而，细胞核内丝状（F-）肌动蛋白（filamentous (F-) actin）的丰度与功能仍存在争议。本研究表明，基于肌动蛋白的分子马达肌球蛋白VI（myosin VI）可参与稳定停滞或逆转的复制叉。在DNA复制应激（DNA replication stress）条件下，肌球蛋白VI会结合停滞的复制中间体，并与AAA ATP酶WRNIP1（AAA ATPase WRNIP1）协同作用，保护这些结构免受DNA2介导的核酸酶降解。研究人员利用功能化锚蛋白重复序列蛋白（functionalized DARPins）以区室特异性方式调控肌球蛋白VI的表达水平，为肌球蛋白VI直接参与细胞核内的复制应激应答提供了实验证据，同时否定了丰富的细胞质肌球蛋白VI池在此复制应激应答过程中的贡献。