Molecular mechanisms of transcriptional regulation by Poly(ADP-ribose) polymerase 1

Abstract

Poly-ADP-ribosylation is a covalent posttranslational modification of nuclear proteins that plays a key role in the immediate cell response to genotoxic stress. Poly(ADP-ribose) polymerases (PARPs) synthesize long and branched ADP-ribose polymers on acceptor regulatory proteins, thereby changing their activity. Poly-ADP metabolism regulates DNA repair, the cell cycle, replication, cell senescence and death, a remodeling of the chromatin structure, and gene transcription. PARP1 is one of the most common nuclear proteins and is responsible for producing ∼90% of all ADP-ribose polymers in the cell. PARP1 inhibitors are promising as antitumor agents. At the same time, current inhibitors targeting the catalytic domain of PARP1 have a number of side effects. Considering the potential benefits PARP1 inhibitors may offer for treating many diseases, it is necessary to develop new strategies of PARP1 inhibition. PARP1 has a modular structure and possesses catalytic, transcription, and DNA-binding activities. The review focuses primarily on the role PARP1 plays in regulating transcription. The structure and functional organization of PARP1 and multiple pathways of the PARP1-dependent transcriptional regulation at the levels of chromatin remodeling, DNA methylation, and transcription are considered in detail. Studying the molecular mechanisms that regulate these processes can provide a basis for a search and design of new PARP1 inhibitors.