PARP1 and Poly(ADP-ribosyl)ation Signaling during Autophagy in Response to Nutrient Deprivation

Figure 1

The intensity of the stimulus that induces DNA damage and the degree of activation of PARP1 determines the fate of a cell toward survival or death. Destination 1. When a slight damage occurs in DNA by endogenous or exogenous agents, PARP1 recognizes these damage points; PARylates itself, histones, and structural chromatin-related proteins; and finally promotes recruitment of DNA repair enzymes. If the DNA is repaired successfully, cells will survive. The effect on nuclear NAD⁺/ATP never leads to energy collapse. Destination 2. Multiple intense damage that despite the activity of PARP1 never will be repaired successfully. The cell enters in irreversible apoptosis, effector caspases 3 and 7 degrade PARP1 as the main competitor for the ATP, and the “eat-me” signal will appear on the cell surface. Destination 3. Excessive DNA damages, though not necessarily lethal, produce a phenomenon of overactivation of PARP1 and over-PARylation in nucleus. The energy consequences are lethal for cells, and the nuclear pool of NAD⁺/ATP will be seriously affected. Poly(ADP-ribose) glycohydrolases and ADP-ribose hydrolases mediate a rapid turnover and recycling of the bulk of PAR modification on nuclear PARylated proteins, autoPARylated PARPs, and free chains of ADP-ribose. The free monomers and little PAR chains are exported to cytosol to induce mitochondrial AIF translocation to nucleus. Finally, cell will die in a non-caspase-dependent process or PARthanatos. Overactivation of PARP1 consumes both NAD⁺ and ATP in nucleus triggering a high imbalance in the total pool of energy in the cells. This total energy collapse alters the functions of the main energy organelles such as mitochondria, ribosomes, or endosomes, favoring a total energy imbalance. At the same time, the presence of PAR chains and free ADP-ribose monomers in the cytosol modifies enzymes such as RIP1, triggering necroptosis. As an alternative to death by necroptosis, autophagy appears as an adaptive pathway to try to alleviate the energy crisis and prevent cell death arising. The nature of the stimulus and its durability will determine recycling of damage organelles, misfolded proteins, or lipid aggregates. PARylation could be considered a highly dynamic posttranslational modification of several proteins forming the autophagosome core or targeting intracellular components to be degraded. At the same time, cells are given an alternative source of energy until the damage is repaired or the stress situation ceases.