FUS RRM 调节转录停滞和 DNA 损伤时 PARP-1 激活后多聚（ADP-核糖）的水平。
FUS RRM regulates poly(ADP-ribose) levels after transcriptional arrest and PARP-1 activation on DNA damage.
机构信息
SABNP, University Evry, INSERM U1204, Université Paris-Saclay, 91025 Evry, France; Institute of Chemical Biology and Fundamental Medicine SB RAS, Lavrentiev Av. 8, Novosibirsk 630090, Russia; Department of Natural Sciences, Novosibirsk State University, 2 Pirogov Street, Novosibirsk 630090, Russia.
SABNP, University Evry, INSERM U1204, Université Paris-Saclay, 91025 Evry, France.
出版信息
Cell Rep. 2023 Oct 31;42(10):113199. doi: 10.1016/j.celrep.2023.113199. Epub 2023 Oct 5.
PARP-1 activation at DNA damage sites leads to the synthesis of long poly(ADP-ribose) (PAR) chains, which serve as a signal for DNA repair. Here we show that FUS, an RNA-binding protein, is specifically directed to PAR through its RNA recognition motif (RRM) to increase PAR synthesis by PARP-1 in HeLa cells after genotoxic stress. Using a structural approach, we also identify specific residues located in the FUS RRM, which can be PARylated by PARP-1 to control the level of PAR synthesis. Based on the results of this work, we propose a model in which, following a transcriptional arrest that releases FUS from nascent mRNA, FUS can be recruited by PARP-1 activated by DNA damage to stimulate PAR synthesis. We anticipate that this model offers new perspectives to understand the role of FET proteins in cancers and in certain neurodegenerative diseases such as amyotrophic lateral sclerosis.
PARP-1 在 DNA 损伤部位被激活，导致长聚（ADP-核糖）（PAR）链的合成，这些链作为 DNA 修复的信号。在这里，我们表明 RNA 结合蛋白 FUS 通过其 RNA 识别基序（RRM）被特异性地引导到 PAR 上，以在 HeLa 细胞受到遗传毒性应激后增加 PARP-1 介导的 PAR 合成。使用结构方法，我们还鉴定了位于 FUS RRM 中的特定残基，这些残基可被 PARP-1 聚 PAR 化，以控制 PAR 合成的水平。基于这项工作的结果，我们提出了一个模型，即在转录停滞释放出结合在新生 mRNA 上的 FUS 后，FUS 可以被由 DNA 损伤激活的 PARP-1 募集，以刺激 PAR 合成。我们预计，该模型为理解 FET 蛋白在癌症以及某些神经退行性疾病（如肌萎缩侧索硬化症）中的作用提供了新的视角。
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