DNA-Independent PARP-1 Activation by Phosphorylated ERK2 Increases Elk1 Activity: A Link to Histone Acetylation

Abstract

PolyADP-ribose polymerases (PARPs) catalyze a posttranslational modification of nuclear proteins by polyADP-ribosylation. The catalytic activity of the abundant nuclear protein PARP-1 is stimulated by DNA strand breaks, and PARP-1 activation is required for initiation of DNA repair. Here we show that PARP-1 also acts within extracellular signal-regulated kinase (ERK) signaling cascade that mediates growth and differentiation. The findings reveal an alternative mode of PARP-1 activation, which does not involve binding to DNA or DNA damage. In a cell-free system, recombinant PARP-1 was intensively activated and thereby polyADP-ribosylated by a direct interaction with phosphorylated ERK2, and the activated PARP-1 dramatically increased ERK2-catalyzed phosphorylation of the transcription factor Elk1. In cortical neurons treated with nerve growth factors and in stimulated cardiomyocytes, PARP-1 activation enhanced ERK-induced Elk1-phosphorylation, core histone acetylation, and transcription of the Elk1-target gene c-fos. These findings constitute evidence for PARP-1 activity within the ERK signal-transduction pathway.

The role of p38 signaling and poly(ADP-ribosyl)ation-induced metabolic collapse in the osteogenic differentiation-coupled cell death pathway

“…However, several alternative mechanisms leading to the activation of PARP1 in the absence of DNA damage have also been described [39][40][41][42]. Here we have shown that a low concentration of hydrogen peroxide produced "physiologically" by cells induced to undergo osteodifferentiation is sufficient to induce DNA breakage as evidenced by the comet assay.…”

Histone H1 Poly[ADP]-Ribosylation Regulates the Chromatin Alterations Required for Learning Consolidation

“…Thus, PARP-1 contributes to NF-B activation in the inflammatory response, provoking CREB binding protein recruitment independent of poly[ADP]-ribosylation (Hassa et al, 2005). In contrast, PARP-1 enzymatic activity is need for the recruitment of coactivators to Elk-1 and Hes-1 during neuronal activation and neurogenesis, respectively (Ju et al, 2004;Cohen-Armon et al, 2007). It has also been shown that PARP-1 contributes to chromatin remodeling and gene transcription in Drosophila under certain physiological conditions (Tulin and Spradling, 2003), probably by releasing histone H1 from specific promoters (Krishnakumar et al, 2008).…”

Regulation of chromatin by histone modifications

“…Presumably, this is a consequence, at least in part, of the negative charge that the modification confers to the histone. In addition, though, it has been reported that the activation of PARP-1 leads to elevated levels of core histone acetylation [39]. Moreover, PARP-1-mediated ribosylation of the H3K4me3 demethylase KDM5B inhibits the demethylase and excludes it from chromatin, while simultaneously excluding H1, thereby making target promoters more accessible [40].…”