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Poly-(ADP-ribose) polymerase-1 is necessary for long-term facilitation in Aplysia.

ABSTRACT: Activity-dependent long-term synaptic plasticity requires gene expression and protein synthesis. Identifying essential genes and studying their transcriptional and translational regulation are key steps to understanding how synaptic changes become long lasting. Recently, the enzyme poly-(ADP-ribose) polymerase 1 (PARP-1) was shown to be necessary for long-term memory (LTM) in Aplysia. Since PARP-1 decondenses chromatin, we hypothesize that this enzyme regulates the expression of specific genes essential for long-term synaptic plasticity that underlies LTM. We cloned Aplysia PARP-1 (ApPARP-1) and determined that its expression in sensory neurons is necessary for serotonin (5-HT)-mediated long-term facilitation (LTF) of sensorimotor neuron synapses. PARP enzymatic activity is also required, since transient application of PARP inhibitors blocked LTF. Differential display and RNA analysis of ganglia dissected from intact animals exposed to 5-HT identified the ribosomal RNA genes as PARP-dependent effector genes. The increase in the expression of rRNAs is long lasting and dynamic. Pulse-labeling RNA studies showed a PARP-dependent increase in rRNAs but not in the total RNA 24 h after 5-HT treatment. Moreover, the expression of both the AprpL27a (Aplysia ribosomal protein L27a) and the ApE2N (Aplysia ubiquitin-conjugating enzyme E2N) mRNAs also increased after 5-HT. Thus, our results suggest that 5-HT, in part by regulating PARP-1 activity, alters the expression of transcripts required for the synthesis of new ribosomes necessary for LTF.

SUBMITTER: Hernandez AI

PROVIDER: S-EPMC6666525 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Poly-(ADP-ribose) polymerase-1 is necessary for long-term facilitation in Aplysia.

Hernández A Iván AI Wolk Jason J Hu Jiang-Yuan JY Liu Jinming J Kurosu Takeshi T Schwartz James H JH Schacher Samuel S

The Journal of neuroscience : the official journal of the Society for Neuroscience 20090701 30

Activity-dependent long-term synaptic plasticity requires gene expression and protein synthesis. Identifying essential genes and studying their transcriptional and translational regulation are key steps to understanding how synaptic changes become long lasting. Recently, the enzyme poly-(ADP-ribose) polymerase 1 (PARP-1) was shown to be necessary for long-term memory (LTM) in Aplysia. Since PARP-1 decondenses chromatin, we hypothesize that this enzyme regulates the expression of specific genes e ...[more]

PMID: 19641118

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Project description:Poly(ADP-ribose) polymerases (PARPs) are involved in many aspects of the cellular response to various forms of damage. PARP-1 and PARP-2, the most abundant PARPs, are central to the response to specific types of DNA damage, especially single-strand breaks. Inhibition of PARP activity may sensitize the cell to exogenous agents such as chemotherapy and radiation. In circumstances where rescue pathways are deficient, particularly the homologous recombination (HR)-directed DNA repair pathway, inhibition of PARP may result in "synthetic lethality." BRCA mutation-associated breast cancers are a paradigm of HR-directed repair deficient tumors. Early clinical trials have demonstrated significant activity of single-agent PARP inhibitors in BRCA-deficient breast and ovarian cancer. Because of phenotypic similarities between some "triple-negative" breast cancers (TNBC) and the most prevalent type of breast cancer seen in BRCA1 mutation carriers, some have hypothesized that TNBC might also be specifically sensitive to PARP inhibition. The activity of single-agent PARP inhibitors in TNBC has not been reported. One trial did suggest significant enhancement of the activity of platinum-based combination chemotherapy, without incremental toxicity. These studies indicate that PARP inhibition is an exciting new approach to the treatment of breast cancers in women with underlying BRCA mutations and possibly in sporadic cancers with defects in HR-directed repair. Future studies will be necessary to determine whether the effectiveness of PARP inhibitors in nonhereditary cancer requires an underlying HR defect or whether these agents may improve the activity of conventional chemotherapy by other means. In addition, studies will be required to determine whether PARP inhibitors may induce synthetic lethality in tumors with defects in pathways other than the BRCA-dependent DNA repair pathway. If either or both of these prove to be the case, then PARP inhibition may benefit a wide spectrum of cancer patients.

Dataset Information

Poly-(ADP-ribose) polymerase-1 is necessary for long-term facilitation in Aplysia.

Publications

Poly-(ADP-ribose) polymerase-1 is necessary for long-term facilitation in Aplysia.

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