长非编码 RNA BS-DRL1 通过与神经元中的 HMGB1 相互作用调节 DNA 损伤反应和基因组稳定性。

Long noncoding RNA BS-DRL1 modulates the DNA damage response and genome stability by interacting with HMGB1 in neurons.

机构信息

Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese academy of Science, Shanghai, 200032, China.

University of Chinese Academy of Sciences, Beijing, China.

出版信息

Nat Commun. 2021 Jul 1;12(1):4075. doi: 10.1038/s41467-021-24236-z.

Long noncoding RNAs (lncRNAs) are known to regulate DNA damage response (DDR) and genome stability in proliferative cells. However, it remains unknown whether lncRNAs are involved in these vital biological processes in post-mitotic neurons. Here, we report and characterize a lncRNA, termed Brain Specific DNA-damage Related lncRNA1 (BS-DRL1), in the central nervous system. BS-DRL1 is a brain-specific lncRNA and depletion of BS-DRL1 in neurons leads to impaired DDR upon etoposide treatment in vitro. Mechanistically, BS-DRL1 interacts with HMGB1, a chromatin protein that is important for genome stability, and is essential for the assembly of HMGB1 on chromatin. BS-DRL1 mediated DDR exhibits cell-type specificity in the cortex and cerebellum in gamma-irradiated mice and BS-DRL1 knockout mice show impaired motor function and concomitant purkinje cell degeneration. Our study extends the understanding of lncRNAs in DDR and genome stability and implies a protective role of lncRNA against neurodegeneration.

长链非编码 RNA（lncRNAs）已知可调节有丝分裂细胞中的 DNA 损伤反应（DDR）和基因组稳定性。然而，lncRNAs 是否参与后有丝分裂神经元中的这些重要生物学过程仍不清楚。在这里，我们在中枢神经系统中报告并描述了一种称为脑特异性 DNA 损伤相关 lncRNA1（BS-DRL1）的 lncRNA。BS-DRL1 是一种脑特异性 lncRNA，神经元中 BS-DRL1 的耗竭会导致体外依托泊苷处理时 DDR 受损。从机制上讲，BS-DRL1 与 HMGB1 相互作用，HMGB1 是一种对基因组稳定性很重要的染色质蛋白，并且是 HMGB1 在染色质上组装所必需的。BS-DRL1 介导的 DDR 在γ辐射小鼠的皮层和小脑中表现出细胞类型特异性，并且 BS-DRL1 敲除小鼠表现出运动功能受损和浦肯野细胞退化。我们的研究扩展了对 DDR 和基因组稳定性中 lncRNA 的理解，并暗示 lncRNA 对神经退行性变具有保护作用。