Divison of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
Nat Commun. 2022 Nov 1;13(1):6531. doi: 10.1038/s41467-022-34310-9.
DNA replication forks are tightly controlled by a large protein network consisting of well-known core regulators and many accessory factors which remain functionally undefined. In this study, we report previously unknown nuclear functions of the actin-binding factor profilin-1 (PFN1) in DNA replication, which occur in a context-dependent fashion and require its binding to poly-L-proline (PLP)-containing proteins instead of actin. In unperturbed cells, PFN1 increases DNA replication initiation and accelerates fork progression by binding and stimulating the PLP-containing nucleosome remodeler SNF2H. Under replication stress, PFN1/SNF2H increases fork stalling and functionally collaborates with fork reversal enzymes to enable the over-resection of unprotected forks. In addition, PFN1 binds and functionally attenuates the PLP-containing fork protector BODL1 to increase the resection of a subset of stressed forks. Accordingly, raising nuclear PFN1 level decreases genome stability and cell survival during replication stress. Thus, PFN1 is a multi-functional regulator of DNA replication with exploitable anticancer potential.
DNA 复制叉受到由众多知名核心调控因子和许多功能尚未明确的辅助因子组成的大型蛋白质网络的严格控制。在这项研究中，我们报告了肌动蛋白结合因子 Profilin-1（PFN1）在 DNA 复制中以前未知的核功能，这些功能以依赖于上下文的方式发生，并且需要其与含有多聚-L-脯氨酸（PLP）的蛋白质而不是肌动蛋白结合。在未受干扰的细胞中，PFN1 通过与含有 PLP 的核小体重塑酶 SNF2H 结合并刺激其活性，增加 DNA 复制起始并加速叉进展。在复制应激下，PFN1/SNF2H 增加叉停滞，并与叉反转酶协同发挥功能，从而使未受保护的叉过度切除。此外，PFN1 与含有 PLP 的叉保护蛋白 BODL1 结合并使其功能失活，从而增加一部分受应激的叉的切除。因此，提高核 PFN1 水平会降低复制应激期间的基因组稳定性和细胞存活率。因此，PFN1 是 DNA 复制的多功能调节剂，具有可开发的抗癌潜力。
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