Parp

• PARP enzymes are essential for DNA repair, particularly single-strand break repair.
• They help maintain genomic stability and prevent mutations in cellular DNA.
• PARP inhibitors block PARP activity, leading to an accumulation of DNA damage in cancer cells.
• This mechanism is especially effective in cancers with existing DNA repair deficiencies, such as those with BRCA mutations.
• PARP inhibitors represent a significant advancement in precision oncology, offering targeted treatment options.

What is PARP (Poly ADP-Ribose Polymerase)?

PARP (Poly ADP-Ribose Polymerase) is a family of enzymes found predominantly in the nucleus of eukaryotic cells, playing a pivotal role in various cellular processes, most notably DNA repair. These enzymes detect and bind to DNA damage, initiating a cascade of events that recruit other repair proteins to the site of injury. Their primary function involves the transfer of ADP-ribose units from NAD+ to target proteins, a process known as poly(ADP-ribosyl)ation. This modification alters the function of recipient proteins, facilitating their involvement in DNA repair, replication, and transcription.

There are 17 known PARP family members, but PARP1 and PARP2 are the most extensively studied due to their critical involvement in the repair of single-strand DNA breaks (SSBs). When an SSB occurs, PARP1 rapidly binds to the damaged site, acting as an immediate sensor. This binding activates PARP1, leading to the synthesis of poly(ADP-ribose) (PAR) chains on itself and other proteins. These PAR chains serve as a signal, attracting and coordinating the assembly of the base excision repair (BER) pathway machinery, which is responsible for fixing SSBs.

PARP’s Role in DNA Repair and Cellular Function

The role of PARP in DNA repair is fundamental for cellular survival and genomic stability. PARP enzymes are central to the base excision repair (BER) pathway, which is the primary mechanism for repairing common types of DNA damage, including oxidative damage, alkylation, and single-strand breaks. Without functional PARP, these minor DNA lesions can accumulate and progress into more severe double-strand breaks (DSBs) during DNA replication. DSBs are highly cytotoxic and can lead to chromosomal instability, mutations, and cell death if not properly repaired.

Beyond DNA repair, PARP function in cells extends to several other crucial cellular processes. These include:

• Transcriptional regulation
• Chromatin structure modulation
• Cell cycle control
• Programmed cell death (apoptosis)

For instance, PARP1 can influence gene expression by modifying histones and other chromatin-associated proteins, thereby altering chromatin accessibility. Its involvement in these diverse pathways underscores its importance in maintaining overall cellular homeostasis and responding to various cellular stresses. The enzyme’s ability to rapidly respond to DNA damage ensures that the cell’s genetic information remains intact, preventing the accumulation of harmful mutations that can drive diseases like cancer.

Mechanism of PARP Inhibitors

The PARP inhibitors mechanism of action involves blocking the activity of PARP enzymes, primarily PARP1 and PARP2. These therapeutic agents are designed to trap PARP enzymes on DNA damage sites, preventing them from dissociating and allowing the repair process to proceed. This “PARP trapping” is a crucial aspect of their efficacy, as the trapped PARP-DNA complexes are highly toxic to cells, especially during DNA replication. When a cell attempts to replicate its DNA with trapped PARP-DNA complexes, the replication fork can collapse, leading to the formation of lethal double-strand breaks.

The clinical utility of PARP inhibitors is particularly pronounced in cancer cells that already have defects in other DNA repair pathways, a concept known as synthetic lethality. For example, cancer cells with mutations in BRCA1 or BRCA2 genes have impaired homologous recombination repair (HRR), a major pathway for repairing double-strand breaks. In such cells, inhibiting PARP effectively shuts down another critical DNA repair pathway (BER), leaving the cancer cell with no viable means to repair its DNA damage. This leads to an accumulation of DNA lesions, genomic instability, and ultimately, selective cell death in cancer cells, while healthy cells with intact HRR can still cope with the damage. This targeted approach has revolutionized the treatment of certain cancers, including ovarian, breast, prostate, and pancreatic cancers, particularly in patients with BRCA mutations.