Abstract
Unexpectedly, a post-translational modification of DNA-binding proteins, initiating the cell response to single-strand DNA damage, was also required for long-term memory acquisition in a variety of learning paradigms. Our findings disclose a molecular mechanism based on PARP1-Erk synergism, which may underlie this phenomenon. A stimulation induced PARP1 binding to phosphorylated Erk2 in the chromatin of cerebral neurons caused Erk-induced PARP1 activation, rendering transcription factors and promoters of immediate early genes (IEG) accessible to PARP1-bound phosphorylated Erk2. Thus, Erk-induced PARP1 activation mediated IEG expression implicated in long-term memory. PARP1 inhibition, silencing, or genetic deletion abrogated stimulation-induced Erk-recruitment to IEG promoters, gene expression and LTP generation in hippocampal CA3-CA1-connections. Moreover, a predominant binding of PARP1 to single-strand DNA breaks, occluding its Erk binding sites, suppressed IEG expression and prevented the generation of LTP. These findings outline a PARP1-dependent mechanism required for LTP generation, which may be implicated in long-term memory acquisition and in its deterioration in senescence.
Highlights
PolyADP-ribose polymerases (PARPs) catalyze an abundant post-translational modification of nuclear proteins by polyADP-ribosylation
We disclose a molecular mechanism in the chromatin of cerebral neurons, which is activated by stimulation-induced Erk-PARP1 binding and synergistic activity required for immediate early genes (IEG) expression implicated in long-term memory
To examine a possible effect of PARP1 on Longterm potentiation (LTP), hippocampal slices were prepared from WT and PARP1 KO mice (Methods)
Summary
PolyADP-ribose polymerases (PARPs) catalyze an abundant post-translational modification of nuclear proteins by polyADP-ribosylation. Alternative mechanisms of PARP1 activation in the absence of DNA damage were identified in a variety of cell types and cell-free systems They include PARP1 activation by a variety of signal transduction mechanisms inducing intracellular Ca2+ release and activation of phosphorylation cascades[2,7,8,9]. We disclose a molecular mechanism in the chromatin of cerebral neurons, which is activated by stimulation-induced Erk-PARP1 binding and synergistic activity required for immediate early genes (IEG) expression implicated in long-term memory. Identified intra-molecular re-arrangements in DNA-bound PARP1 preventing its binding to phosphorylated Erk[2], interfered with stimulation-induced IEG expression and LTP generation in the presence of DNA single-strand breaks, usually accumulated in aged irreplaceable cerebral neurons[19,20]
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