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

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.

Posttranscriptional Regulation of PARG mRNA by HuR Facilitates DNA Repair and Resistance to PARP Inhibitors

“…Ke and colleagues recently demonstrated that under LPS stimulation, PARP1 directly binds HuR, thus resulting in its PARylation and modulating its nucleocytoplasmic shuttling as well as mRNA target binding(31). Though these findings were established in murine macrophages and human kidney cells, they could potentially have profound implications in carcinogenesis and tumor response, particularly in HuR-mediated stress response pathway.…”

“…Fig. S2A)(31). PARP1 activation, upon genotoxic stress, results in PARylated HuR which not only facilitates its cytoplasmic translocation, but also regulates its target binding(31).…”

“…S2A)(31). PARP1 activation, upon genotoxic stress, results in PARylated HuR which not only facilitates its cytoplasmic translocation, but also regulates its target binding(31). Cytoplasmic HuR selectively binds to several target mRNAs, which could presumably be affected by the degree of PARylation (as well as other PTMs such as phosphorylation, ubiquitination etc.).…”

Connections between 3′ end processing and DNA damage response: Ten years later

“…Consistent with this, recent studies have shown that PARP1‐mediated chromatin modifications affect not only RNAP II elongation but also co‐transcriptional modifications (Matveeva, Al‐Tinawi, Rouchka, & Fondufe‐Mittendorf, ) and that PARP1 is an mRNA‐binding protein (Melikishvili, Chariker, Rouchka, & Fondufe‐Mittendorf, ). Besides, PARP1 binds to and PARylates embryonic lethal abnormal vision‐like 1 (Elavl1)/human antigen R (HuR), allowing its nucleocytoplasmic shuttling and binding to its mRNA targets 3′ ends, increasing their stability (Y. Ke et al, ). Y. Shi et al () also described RBBP6, an E3 ubiquitin ligase originally described to interact with p53 (Simons et al, ), as part of the 3′ end processing molecular architecture.…”

“…Transcriptome wide analysis of samples from cells exposed to IR radiation revealed a decrease in HuR binding to its target mRNAs due to activated CHK2‐mediated phosphorylation (Masuda et al, ). Upon genotoxic stress, HuR can be PARylated by poly(ADP‐ribose) polymerase 1 (PARP1) facilitating its cytoplasmic translocation and regulation of its binding to target mRNAs (Chand et al, ; Gagné et al, ; Y. Ke et al, ). dePARylation of HuR facilitates its release from target mRNAs and its shuttling back into the nucleus.…”