A PARP1-ERK2 synergism is required for the induction of LTP.
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.
Neufeld Cardiac Research institute, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel.
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Visochek
Department of Neurobiology, the Weizmann Institute of Science, Rehovot 76100, Israel.
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Grigoryan
Neufeld Cardiac Research institute, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel.|Department of Physiology and Pharmacology, Tel-Aviv University, Tel-Aviv 69978, Israel.
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Kalal
Department of Physiology and Pharmacology, Tel-Aviv University, Tel-Aviv 69978, Israel.|Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv 69978, Israel.
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Milshtein-Parush
Department of Physiology and Pharmacology, Tel-Aviv University, Tel-Aviv 69978, Israel.|Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv 69978, Israel.
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Gazit
Department of Physiology and Pharmacology, Tel-Aviv University, Tel-Aviv 69978, Israel.|Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv 69978, Israel.
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Slutsky
Bioinformatics Unit, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv 69978, Israel.
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Yeheskel
Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, 52900 Ramat Gan, Israel.
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Shainberg
Cancer Research Center, Sheba Medical Center, 53621 Ramat Gan, Israel.
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Castiel
Department of Biological Regulation, the Weizmann Institute of Science, Rehovot 76100, Israel.
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Seger
Department of Biochemistry and Molecular Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, USA.
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Langelier
Biotechnology and Cell Signaling, UMR7242, Ecole Superieure de Biotechnologie Strasbourg, F-67400, Illkrich-Graffenstaden, France.
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Dantzer
Department of Biochemistry and Molecular Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, USA.
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Pascal
Department of Neurobiology, the Weizmann Institute of Science, Rehovot 76100, Israel.
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Segal
Neufeld Cardiac Research institute, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel.|Department of Physiology and Pharmacology, Tel-Aviv University, Tel-Aviv 69978, Israel.|Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv 69978, Israel.
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Cohen-Armon
D000818:Animals; D056547:CA1 Region, Hippocampal / Q000502:physiology*; D056654:CA3 Region, Hippocampal / Q000502:physiology*; D005786:Gene Expression Regulation; D017774:Long-Term Potentiation; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000378:metabolism*; D011485:Protein Binding
C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1