PARP1 promotes gene expression at the post-transcriptiona level by modulating the RNA-binding protein HuR.
PARP1 promotes gene expression at the post-transcriptiona level by modulating the RNA-binding protein HuR.
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PARP1 通过调节 RNA 结合蛋白 HuR 促进转录后水平的基因表达
DOI：
10.1038/ncomms14632
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发表时间：
2017-03-08
影响因子：
16.6
通讯作者：
Zeng X
中科院分区：
文献类型：
--
作者：
Ke Y;Han Y;Guo X;Wen J;Wang K;Jiang X;Tian X;Ba X;Boldogh I;Zeng X
聚腺苷二磷酸核糖基化(PAR化)主要由聚腺苷二磷酸核糖聚合酶1(PARP1)催化，其在基因转录调控中的作用已被证实。在这里，我们发现，作为对脂多糖暴露的响应，PARP1与富含腺苷尿酸的元件结合蛋白胚胎致死性异常视觉样蛋白1(Elevl1)/人类抗原R(Hur)相互作用，导致其PAR化，主要位于D226位。PARP抑制和D226突变破坏了Hur的PAR化、核质穿梭和mRNA结合。在D226A Hur表达的细胞中，促炎症细胞因子/趋化因子的mRNA水平或稳定性的增加可被PARP1消融或抑制消除，或被阻断。本研究证明了一种在转录后水平调节基因表达的机制，并提示阻断PARP1与HUR的相互作用可能是治疗炎症相关疾病的一种策略，这些疾病涉及增加mRNA的稳定性。
Poly(ADP-ribosyl)ation (PARylation) is mainly catalysed by poly-ADP-ribose polymerase 1 (PARP1), whose role in gene transcription modulation has been well established. Here we show that, in response to LPS exposure, PARP1 interacts with the adenylateuridylate-rich element-binding protein embryonic lethal abnormal vision-like 1 (Elavl1)/human antigen R (HuR), resulting in its PARylation, primarily at site D226. PARP inhibition and the D226 mutation impair HuR’s PARylation, nucleocytoplasmic shuttling and mRNA binding. Increases in mRNA level or stability of pro-inflammatory cytokines/chemokines are abolished by PARP1 ablation or inhibition, or blocked in D226A HuR-expressing cells. The present study demonstrates a mechanism to regulate gene expression at the post-transcriptional level, and suggests that blocking the interaction of PARP1 with HuR could be a strategy to treat inflammation-related diseases that involve increased mRNA stability.