The taming of PARP1 and its impact on NAD+ metabolism
In short, poly (ADP-ribose) polymerase 1 is an essential enzyme involved in various cellular processes. For example, it is activated and recruited to DNA to repair it when it is damaged. To be activated PARP1 consumes the metabolite NAD+. However, if the PARP1 enzyme is over-activated, it over-consumes NAD+, which becomes toxic and leads to cell death. During evolution, an epigenetic* regulator, the macroH2A1.1** protein, evolved to overcome this toxicity of PARP1 by inhibiting its activity. These mechanisms were synthesized in a review written by Dr. Hurtado-Bagès et al, a former PhD student in Marcus Buschbeck's lab (Josep Carreras Research Institute, Spain). In collaboration with the authors of this review, we illustrated their work by designing three figures.
ADP-ribose residues are produced upon NAD+ consumption by the PARP1 enzyme.
Central role of NAD+ maintenance in all cellular compartments.
MacroH2A1.1 is able to inhibit PARP1 activity to some extent.
*Epigenetics: How does a single cell from a fertilized egg manage to give rise to a fully mature organism assembled by multiple cells with specific and diverse functions? Indeed, all these cells have the same DNA copies but read and interpret the DNA information differently. But how? Epigenetics studies heritable and inheritable mechanisms that reversibly and adaptively modify gene expression without changing the DNA sequence. Epigenetic regulators act at different levels to determine whether genes are turned on or silenced.
These include DNA modifiers that add or remove chemicals to the DNA or proteins that organize the level of DNA folding. These mechanisms have a crucial impact on how organisms manage to adapt to their environment. Nowadays, researchers are still trying to decipher this epigenetic code.
**MacroH2A1.1: In our cells, two meters of DNA are packed to fit in small nuclei (about 10 nanometer). How is it packed? It is wrapped around eight proteins called histones. This complex, made up of DNA and histone proteins, is known as the nucleosome. MacroH2A1.1 is a histone variant that can be part of such a nucleosome under particular conditions. Its structural and physicochemical characteristics confer a specific function to the DNA where it is located.