Department of Biomedical Science, School of Life Science, CHA University, Seongnam-si, Gyunggi-do, South Korea.
Department of Dermatology, CHA Bundang Medical Center, CHA University, Seongnam-si, Gyunggi-do, South Korea.
Mol Biol Rep. 2021 Feb;48(2):1439-1452. doi: 10.1007/s11033-021-06210-6. Epub 2021 Feb 15.
Profilin-1 (PFN1) regulates actin polymerization and cytoskeletal growth. Despite the essential roles of PFN1 in cell integration, its subcellular function in keratinocyte has not been elucidated yet. Here we characterize the specific regulation of PFN1 in DNA damage response and repair machinery. PFN1 depletion accelerated DNA damage-mediated apoptosis exhibiting PTEN loss of function instigated by increased phosphorylated inactivation followed by high levels of AKT activation. PFN1 changed its predominant cytoplasmic localization to the nucleus upon DNA damage and subsequently restored the cytoplasmic compartment during the recovery time. Even though γH2AX was recruited at the sites of DNA double strand breaks in response to DNA damage, PFN1-deficient cells failed to recruit DNA repair factors, whereas control cells exhibited significant increases of these genes. Additionally, PFN1 depletion resulted in disruption of PTEN-AKT cascade upon DNA damage and CHK1-mediated cell cycle arrest was not recovered even after the recovery time exhibiting γH2AX accumulation. This might suggest PFN1 roles in regulating DNA damage response and repair machinery to protect cells from DNA damage. Future studies addressing the crosstalk and regulation of PTEN-related DNA damage sensing and repair pathway choice by PFN1 may further aid to identify new mechanistic insights for various DNA repair disorders.
丝状肌动蛋白结合蛋白 1（PFN1）调节肌动蛋白聚合和细胞骨架生长。尽管 PFN1 在细胞整合中起着至关重要的作用，但它在角质形成细胞中的亚细胞功能尚未阐明。在这里，我们描述了 PFN1 在 DNA 损伤反应和修复机制中的特异性调节。PFN1 耗竭加速了 DNA 损伤诱导的细胞凋亡，表现为 AKT 激活水平升高导致的磷酸化失活增加，从而引发 PTEN 功能丧失。DNA 损伤后，PFN1 将其主要的细胞质定位改变为细胞核，随后在恢复期间恢复细胞质区室。尽管 γH2AX 在 DNA 双链断裂部位被募集以响应 DNA 损伤，但 PFN1 缺陷细胞未能募集 DNA 修复因子，而对照细胞则显著增加了这些基因的表达。此外，PFN1 耗竭导致 DNA 损伤后 PTEN-AKT 级联的破坏，即使在恢复时间后，细胞周期阻滞也无法恢复，表现为 γH2AX 积累。这可能表明 PFN1 在调节 DNA 损伤反应和修复机制方面发挥作用，以保护细胞免受 DNA 损伤。未来研究解决 PFN1 对 PTEN 相关 DNA 损伤感应和修复途径选择的相互作用和调节，可能有助于进一步确定各种 DNA 修复障碍的新机制见解。
