PARP-Mediated Gene Regulation <P>

Poly(ADP-ribose) polymerase-1 (PARP-1) is an abundant zinc finger-containing nuclear protein found in most eukaryotes. PARP-1 has long been regarded as an intracellular sensor of DNA strand breaks, and its function has been considered in context with the cellular responses to genotoxic stress, DNA damage repair and apoptosis. Accumulating evidence has also implicated PARP-1 in transcriptional regulation of specific genes following various pathophysiological stimuli such as inflammation, myocardial reperfusion injury, and immunological stress. PARP-1 may exert its function in transcription through direct binding to gene-regulating sequences, modulation of the nucleoprotein architecture of chromatin, or modification of transcription factors by poly(ADP-ribosyl)ation. However, the dependency of PARP-1 function on the presence of strand breaks in DNA provides no clue to a mechanism by which it may bind to gene promoters or ADP-ribosylate transcription regulators and structural chromatin proteins in the absence of DNA damage. The focus of this seminar is on macromolecular interactions between PARP-1 and genomic DNA as a prerequisite for the interpretation of PARP-1 function in normal cell physiology and in immediate-early transcription responses to genotoxic stress.