Work in our laboratory focuses on understanding the mechanisms of chromatin regulation by protein-poly(ADP-ribosyl)ation.
Protein poly(ADP-ribosyl)ation (pADPr) levels are determined by the relative activity of poly(ADP-ribose) polymerase (PARP) and tankyrase enzymes that utilize NAD to add such residues, and poly(ADP-ribose) glycohydrolase (PARG) enzymes that remove them. One of the consequences of this modification for nuclear proteins is the relocation from chromatin to nucleoplasmic bodies (Figure). Poly(ADP-ribosyl)ation of proteins was known for a long time as a posttranscriptional modification that is coupled to DNA repair/apoptosis triggering. Our research revealed vital roles of PARP in transcriptional regulation, and subsequently PARPs have been implicated in a number of developmentally regulated processes such as chromatin remodeling, transcriptional regulation, and telomere elongation. The presence of multiple PARP-related proteins (eighteen) in mammals complicates the analysis and interpretation of results. Fortunately, only a single PARP1 and single tankyrase gene are present in the Drosophila genome, making this animal an invaluable model system to study PARPs functions.
We have demonstrated the vital roles of PARP1 protein in Drosophila development. We found that PARP1 enzymatic activity is required for transcriptional activation of heat shock-dependent, NF-kB-dependent, and ecdisteroid-dependent genes. Also we have demonstrated the requirement of PARP1 for nucleolar function. Our data strongly suggest that PARP1 is involved in transcriptional regulation through induction of chromatin loosening at targeted genetic loci. These functions are distinct from the previously characterized role of PARP1 in DNA repair and apoptosis. The main goal of our current research is to investigate the PARP-dependent regulatory mechanisms that are involved in chromatin and transcription modulation during development.
Our long-term plan is to use the Drosophila system of poly(ADP-ribose) metabolism to understand how a cell can be programmed to undergo quick, local and reversible chromatin reprogramming and how this can be connected to the induction of local gene activity. Eventually, genes located within repressed chromatin might be exposed and made susceptible to re-programming by artificially activating nearby chromosomal PARP molecules. Understanding of how PARP is activated within normal, undamaged chromatin will advance our knowledge of developmental gene regulation and facilitate the development of methods to experimentally re-program genes.