Poly ADP-ribose Polymerase (PARP) is a family of enzymes found in all cells, involved in numerous cellular processes. These proteins maintain the stability of our genetic material, DNA, and contribute to how cells respond to stress. They modify other proteins by adding chains of poly(ADP-ribose), influencing various cellular activities.
The Essential Role of PARP in Cells
PARP enzymes, especially PARP1, are key responders to DNA damage. When a single-strand break is detected, PARP1 binds to the damaged site, changing its structure. This activates PARP1, which synthesizes poly(ADP-ribose) (PAR) chains using NAD+.
These PAR chains signal and attract other repair proteins, such as XRCC1, DNA ligase III, and DNA polymerase beta, to the damage site. This coordinated effort is part of the base excision repair pathway, a mechanism that fixes single-strand breaks and maintains genomic integrity. This function prevents mutations and preserves genomic stability.
PARP’s Involvement in Disease
While PARP’s DNA repair role is normal, its activity can become dysregulated in various diseases, especially cancer. Cancer cells often have defects in their DNA repair systems, such as BRCA1 and BRCA2 mutations. These cells become reliant on PARP for survival, as PARP helps manage increased DNA damage from rapid growth and genetic instabilities.
Overexpression or excessive activation of PARP contributes to cancer by promoting uncontrolled cell growth, evading growth suppressors, and resisting programmed cell death. For instance, PARP1 acts as a transcriptional activator for growth factors that fuel tumor growth. Beyond cancer, PARP overactivation links to inflammatory conditions like lung disorders, cardiovascular disease, and diabetes. In these conditions, PARP influences gene expression related to inflammation and metabolism.
PARP Inhibitors and Their Therapeutic Use
Understanding PARP’s DNA repair role led to PARP inhibitors, a class of cancer therapy drugs. These inhibitors block PARP enzyme activity, preventing repair of single-strand DNA breaks. This inhibition accumulates unrepaired single-strand breaks, which convert into double-strand breaks during DNA replication. Normal cells with intact DNA repair pathways fix these double-strand breaks.
However, cancer cells with defects in other DNA repair pathways, such as BRCA1 or BRCA2 mutations, cannot effectively repair these double-strand breaks. This is “synthetic lethality,” where PARP inhibition, combined with an existing DNA repair deficiency in cancer cells, leads to their selective death, sparing healthy cells. PARP inhibitors are approved for specific cancers, including ovarian, breast, prostate, and pancreatic, especially in patients with BRCA1/2 mutations or other homologous recombination deficiencies. Examples include olaparib, rucaparib, niraparib, and talazoparib. These drugs are often used as maintenance therapy to delay cancer recurrence after initial treatment.