PARP1 promotes gene expression at the post-transcriptional level by modulating the RNA-binding protein HuR

Yueshuang Ke,Ke Wang,Xue Tian,Xianlu Zeng,Istvan Boldogh,Xueqing Ba,Xiaolan Guo,Xue Jiang,Jitao Wen,Yanlong Han

doi:10.1038/ncomms14632

Abstract

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.

Highlights

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
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
These results verified the involvement of PARP1 in messenger RNA (mRNA) stability regulation, and suggested Cxcl[2] mRNA more susceptible to be affected by PARP1 activation

Summary

Introduction

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. 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. The expression of inflammatory genes is tightly regulated by both transcriptional and post-transcriptional mechanisms because modifying messenger RNA (mRNA) stability provides rapid and flexible control, and is important in coordinating the initiation and resolution of inflammation[12]. This urged us to investigate whether PARP1 regulates the expression of inflammatory cytokines/chemokines at the posttranscriptional level. The results presented a mechanism to regulate gene expression at the post-transcriptional level by PARP1 activation

Methods

Results

Conclusion