PARP Proteins in Health and Disease
Prof. Malka Cohen-Armon, D.Sc.
Dept. of Physiology & Pharmacology and the Neufeld Cardiac Research Institute
The general focus of our research is on signal transduction mechanisms implicating PARP (polyADP-ribose polymerase) proteins. PARPs are highly conserved proteins that are involved in a variety of processes, including epigenetic mechanisms, DNA repair, cell cycle and gene expression. PARP-1, the most abundant PARP protein, is activated by binding to single strand DNA breaks. Activated PARP-1 recruits ligazes to the lesion, promoting DNA repair.
One of our contributions to this field was the discovery of alternative mechanisms activating PARP-1 in the absence of DNA breaks. This unveiled a variety of extra-nuclear signals activating PARP proteins in a variety of processes regulating gene expression.
We found that PARP-1 is a target of signal transduction mechanisms activated by intracellular Ca2+ mobilizition or by the MEK-ERK phosphorylation cascade. Moreover, we found that ERK activity in the nucleus is highly up-regulated by activated PARP-1, implicating PARP-1 in ERK-dependent gene expression. Up-regulation of immediate early genes underlying long-term memory formation may underlie the pivotal role of PARP-1 in long-term memory formation during learning. Regulation of gene expression, controlling cell growth and development, may underlie the role of PARP-1 in neuronal remodeling and cardiomyocytes growth.
Recently, we found that a phenanthrene derived PARP inhibitor acts as an extra-centrosomes de-clustering agent, exclusively and efficiently eradicating human cancer cells by ‘mitotic catastrophe’ cell death, without impairing normal cells. Since many human cancer cells depend on extra-centrosomes clustering for their survival, this molecule is now used for developing a novel cancer targeting therapy.