PDF(Pubmed)
Abstract：
The nuclear envelope (NE) creates a barrier between the cytosol and nucleus during interphase that is key for cellular compartmentalization and protecting genomic DNA. NE rupture can expose genomic DNA to the cytosol and allow admixture of the nuclear and cytosolic constituents, a proposed mechanism of cancer and NE-associated diseases. Barrier-to-autointegration factor (BAF) is a DNA-binding protein that localizes to NE ruptures where it recruits LEM-domain proteins, A-type lamins, and participates in rupture repair. To further reveal the mechanisms by which BAF responds to and aids in repairing NE ruptures, we investigated known properties of BAF including LEM domain binding, lamin binding, compartmentalization, phosphoregulation of DNA binding, and BAF dimerization. We demonstrate that it is the cytosolic population of BAF that functionally repairs NE ruptures, and phosphoregulation of BAF\'s DNA-binding that enables its ability to facilitate that repair. Interestingly, BAF\'s LEM or lamin binding activity appears dispensable for its role in functional repair. Furthermore, we demonstrate that BAF functions to reduce the extent of leakage though NE ruptures, suggesting that BAF effectively forms a diffusion barrier prior to NE repair. Collectively, these results enhances our knowledge of the mechanisms by which BAF responds to NE ruptures and facilitates their repair.
摘要：
核膜（NE）在间期期间在细胞质和细胞核之间产生屏障，这是细胞区室化和保护基因组DNA的关键。NE破裂可以将基因组DNA暴露于细胞质，并允许细胞核和胞质成分混合，提出了癌症和NE相关疾病的机制。屏障自动整合因子（BAF）是一种DNA结合蛋白，可定位到NE破裂，在那里它招募LEM结构域蛋白，A型薄片，并参与破裂修复。为了进一步揭示BAF响应和帮助修复NE破裂的机制，我们研究了BAF的已知特性，包括LEM结构域结合，薄片结合，条块分割,DNA结合的磷酸化调节，和BAF二聚化。我们证明了BAF的胞质种群在功能上修复了NE破裂，和磷酸化调节BAF的DNA结合，使其能够促进修复。有趣的是,BAF的LEM或lamin结合活性在功能修复中的作用似乎是可有可无的。此外，我们证明了BAF的功能是减少NE破裂时泄漏的程度，表明BAF在NE修复之前有效地形成了扩散屏障。总的来说，这些结果增强了我们对BAF响应NE破裂并促进其修复的机制的认识。
