Poly (ADP-ribose) polymerase (PARP) is a family of proteins involved in a number of cellular processes such as
DNA repair and programmed cell death. The most studied member of this family is PARP-1, which plays a critical role in the repair of single-strand DNA breaks. PARP detects DNA damage and signals for repair by attaching ADP-ribose units to itself and other nuclear proteins, a process known as PARylation.
PARP is activated by DNA strand breaks. Upon activation, PARP catalyzes the transfer of ADP-ribose units from
NAD+ (nicotinamide adenine dinucleotide) to target proteins, forming long branched chains of poly(ADP-ribose). This post-translational modification serves as a platform for the recruitment of
DNA repair proteins like XRCC1, DNA ligase III, and DNA polymerase beta, which collaboratively restore DNA integrity.
Inhibition of PARP activity can lead to the accumulation of DNA damage, ultimately triggering
cell death pathways such as apoptosis. PARP inhibitors have been developed as a therapeutic strategy in cancer treatment, particularly targeting tumors with existing defects in homologous recombination repair, like those with BRCA1 or BRCA2 mutations. By blocking PARP, cancer cells are unable to efficiently repair DNA damage, leading to cell death, while normal cells with intact repair pathways are less affected.
PARP inhibitors are especially effective in cancers with deficiencies in DNA repair mechanisms. This concept is known as
synthetic lethality, where two concurrent defects (in this case, BRCA mutation and PARP inhibition) result in cell death. Drugs like olaparib, rucaparib, and niraparib are approved for treating ovarian and breast cancers with BRCA mutations. These drugs exploit the reliance of cancer cells on PARP-mediated repair due to their compromised alternative DNA repair pathways.
Beyond DNA repair, PARP is involved in the regulation of
gene expression, chromatin structure, and cellular stress responses. By modifying chromatin-associated proteins, PARP can influence chromatin remodeling and thereby affect transcriptional regulation. Moreover, PARP activity is implicated in the inflammatory response and metabolic regulation, demonstrating its multifaceted role in cellular homeostasis.
While PARP inhibitors offer a promising approach for cancer treatment, they can also cause adverse effects. Common side effects include nausea, fatigue, and hematological toxicities such as anemia and thrombocytopenia. Long-term use may lead to the development of resistance, as cancer cells adapt by restoring homologous recombination or finding alternative repair pathways. Therefore, ongoing research is focused on understanding resistance mechanisms and optimizing combination therapies.
PARP is involved in various forms of cell death, including apoptosis and necroptosis. Overactivation of PARP, such as during extensive DNA damage, can lead to a depletion of cellular NAD+ and ATP, driving cells towards necrosis. Alternatively, PARP can facilitate apoptosis by modulating apoptotic signaling pathways. This dual role highlights the complex interplay between
DNA damage response and cell fate determination.
Conclusion
PARP is a crucial player in maintaining genomic stability and orchestrating cellular responses to DNA damage. Its role in DNA repair and cell death makes it a valuable target in cancer therapy, particularly for tumors with inherent DNA repair defects. However, the broad implications of PARP activity in cell biology necessitate a deeper understanding to better exploit its potential in therapeutic interventions while minimizing adverse effects.
