Poly (ADP-ribose) polymerase, or PARP, represents a family of proteins that fulfill numerous roles within cells. These proteins are fundamental for maintaining the cell’s internal balance and ensuring its proper functioning. Found across all domains of life, PARPs contribute to the stability of an organism’s cellular machinery and overall cellular integrity.
Understanding PARP Proteins
PARP stands for Poly ADP-ribose polymerase. These proteins primarily function as enzymes located within the cell’s nucleus. Their main enzymatic action, called “PARylation,” involves transferring ADP-ribose units from NAD+ onto target proteins. This creates long, branched chains of poly(ADP-ribose), or PAR, which vary in length and structure.
There are 17 known members in the human PARP family, each with distinct functions; PARP-1 is the most extensively studied. Some PARP enzymes are mono(ADP-ribose) transferases, adding only a single ADP-ribose unit, while others form very short chains. The formation of these PAR chains acts as a signal, influencing the activity and interactions of other proteins within the cell.
PARP’s Role in Cellular Health
A primary function of PARP proteins is their involvement in DNA damage repair. When DNA experiences a single-strand break, PARP proteins, particularly PARP-1, quickly detect and bind to the damaged site. This binding causes a structural change in PARP, initiating the synthesis of a poly(ADP-ribose) chain.
This PAR chain serves as a signal to recruit other DNA repair proteins to the damaged site. This coordinated effort assembles the machinery for processes like base excision repair (BER), which mends single-strand breaks. After signaling, PARP-1 detaches from the DNA, allowing repair enzymes to complete their work and restore genomic stability.
PARP Proteins and Disease Development
Alterations in PARP function can contribute to the development of various diseases, particularly cancer. While PARP normally maintains genomic integrity by repairing DNA, its activity can be exploited by cancer cells, or its dysfunction can lead to mutations that drive cancer progression. For instance, PARP-1 is often upregulated in certain cancers.
Cancer cells often have existing defects in their DNA repair pathways, making them highly dependent on PARP for survival. This reliance creates a situation known as “synthetic lethality,” where the combination of two non-lethal weaknesses—the cancer cell’s inherent DNA repair deficiency and the inhibition of PARP—results in the cancer cell’s death. This concept is particularly relevant in cancer cells with mutations in genes like BRCA1 or BRCA2, which are involved in homologous recombination, another major DNA repair pathway.
PARP Inhibitors in Medicine
PARP inhibitors are a class of targeted therapies used in cancer treatment, particularly for tumors with existing DNA repair deficiencies. These drugs work by blocking the enzymatic activity of PARP proteins, preventing them from repairing damaged DNA in cancer cells. By inhibiting PARP, these drugs cause DNA damage to accumulate to a point where the cancer cells can no longer survive and undergo cell death.
The mechanism of action often involves “PARP trapping.” Here, inhibitors not only block PARP’s catalytic activity but also trap PARP molecules on DNA lesions. These trapped PARP-DNA complexes can lead to the collapse of replication forks, resulting in severe double-strand breaks that compromised cancer cells cannot repair.
PARP inhibitors have received approval for treating various cancers, including ovarian, breast, prostate, and pancreatic cancers, especially in patients with BRCA1/2 mutations. They are often used as maintenance therapy after initial treatments to help delay cancer recurrence. Researchers are also exploring their potential in other cancer types and in combination with other therapies like chemotherapy or immunotherapy.