TAR DNA-binding protein 43 (TDP-43; also known as TARDBP) is an RNA-binding protein whose aggregation is a hallmark of the neurodegenerative disorders amyotrophic lateral sclerosis and frontotemporal dementia. TDP-43 loss increases DNA damage and compromises cell viability, but the actual function of TDP-43 in preventing genome instability remains unclear. Here, we show that loss of TDP-43 increases R-loop formation in a transcription-dependent manner and results in DNA replication stress. TDP-43 nucleic-acid-binding and self-assembly activities are important in inhibiting R-loop accumulation and preserving normal DNA replication. We also found that TDP-43 cytoplasmic aggregation impairs TDP-43 function in R-loop regulation. Furthermore, increased R-loop accumulation and DNA damage is observed in neurons upon loss of TDP-43. Together, our findings indicate that TDP-43 function and normal protein homeostasis are crucial in maintaining genomic stability through a co-transcriptional process that prevents aberrant R-loop accumulation. We propose that the increased R-loop formation and genomic instability associated with TDP-43 loss are linked to the pathogenesis of TDP-43 proteinopathies.

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TAR DNA 结合蛋白 43（TDP-43；也称为 TARDBP）是一种 RNA 结合蛋白，其聚集是神经退行性疾病肌萎缩侧索硬化症和额颞叶痴呆的标志。TDP-43 缺失会增加 DNA 损伤并损害细胞活力，但 TDP-43 在防止基因组不稳定方面的实际功能仍不清楚。在这里，我们发现 TDP-43 的缺失以转录依赖性方式增加 R 环的形成，并导致 DNA 复制应激。TDP-43 核酸结合和自组装活性对于抑制 R 环积累和保持正常 DNA 复制非常重要。我们还发现 TDP-43 细胞质聚集会损害 TDP-43 在 R 环调节中的功能。此外，在失去 TDP-43 后，在神经元中观察到 R 环积累和 DNA 损伤增加。总之，我们的研究结果表明，TDP-43 功能和正常的蛋白质稳态对于通过防止异常 R 环积累的共转录过程维持基因组稳定性至关重要。我们认为，与 TDP-43 缺失相关的 R 环形成增加和基因组不稳定性与 TDP-43 蛋白病的发病机制有关。

本文有对该论文第一作者的相关第一人称采访。