Poly(ADP-ribose) (PAR) is a complex molecule found within cells, involved in various biological processes. Understanding PAR’s role in maintaining cellular health and genetic material is key to comprehending fundamental cellular mechanisms.
Understanding Poly(ADP-ribose)
Poly(ADP-ribose) is a chain-like molecule of repeating ADP-ribose units, a building block derived from nicotinamide adenine dinucleotide (NAD+). These chains can reach up to 200 units and include branch points. The addition of these ADP-ribose units to target proteins is known as poly-ADP-ribosylation or PARylation.
The formation of PAR is catalyzed by a family of enzymes, the poly(ADP-ribose) polymerases (PARPs). PARP1 is the most abundant and well-characterized. PARPs transfer ADP-ribose from NAD+ to proteins like histones and transcription factors. Conversely, poly(ADP-ribose) glycohydrolase (PARG) breaks down PAR chains by hydrolyzing ribose-ribose bonds. This dynamic balance between PARP and PARG activity is important for proper cellular function.
Essential Roles of Poly(ADP-ribose)
PAR is primarily involved in DNA repair, especially single-strand breaks. When DNA damage occurs, PARP enzymes, particularly PARP1, detect and bind to the damaged DNA. This activates PARP1, prompting it to synthesize PAR chains on itself and other nearby proteins.
PAR chains signal and recruit DNA repair proteins to the damage site. These include base excision repair (BER) proteins like DNA ligase III, DNA polymerase beta, and XRCC1. Accumulated PAR chains also loosen chromatin, making DNA more accessible for repair. After repair, PARG degrades the chains, allowing repair proteins to dissociate and chromatin to return to normal.
Beyond DNA repair, PAR regulates gene expression. PARP1 modifies histones, which are proteins around which DNA is wound. This leads to chromatin relaxation, allowing transcription complexes to access genes. PARPs also influence RNA-binding proteins, regulating RNA processing, translation, and decay. PAR also participates in programmed cell death (apoptosis) and the inflammatory response. Excessive PAR accumulation can lead to cell death by depleting cellular energy stores (NAD+ and ATP) or by stimulating the release of apoptosis-inducing factors from mitochondria.
Poly(ADP-ribose) in Health and Disease
Dysregulation of PAR metabolism links to various health conditions. Altered PARP activity is common in cancer. Enhanced PARP expression is observed in tumor types like melanoma, lung, and breast cancers, associating with poorer survival and treatment resistance. PAR’s support for DNA repair can inadvertently help cancer cells survive damage from chemotherapy or radiation.
PAR also has implications in neurodegenerative diseases like Parkinson’s (PD) and Alzheimer’s (AD). Overactivation of PARP1, often triggered by DNA damage or oxidative stress, leads to excessive PAR accumulation. This accumulation can trigger parthanatos, a specific type of cell death, contributing to neuronal loss. For example, in Parkinson’s, pathologic alpha-synuclein activates PARP-1. The resulting PAR generation accelerates the formation of more toxic alpha-synuclein, leading to cell death.
Imbalances in PAR metabolism are also implicated in aging and metabolic disorders. While supporting genomic integrity through DNA repair, PARP activation can limit metabolic fitness and increase susceptibility to metabolic diseases. Studies in accelerated aging models, like Cockayne Syndrome, show impaired DNA repair leads to increased PARylation, mitochondrial dysfunction, and accelerated aging.
Targeting Poly(ADP-ribose) for Therapy
Understanding PAR’s functions has opened therapeutic avenues, particularly in cancer. Poly(ADP-ribose) polymerase inhibitors (PARP inhibitors) block the activity of PARP enzymes, primarily PARP1 and PARP2. These inhibitors show efficacy in various cancers, especially those with DNA repair defects, such as BRCA1 or BRCA2 gene mutations.
This therapeutic approach relies on the concept of “synthetic lethality.” In cancer cells with a faulty BRCA gene, the homologous recombination (HR) DNA repair pathway is compromised. Inhibiting PARP, which repairs single-strand DNA breaks, causes these breaks to accumulate and convert into more severe double-strand breaks during DNA replication. Since the HR pathway is already defective, cancer cells cannot repair these extensive breaks, leading to their death. Normal cells with intact HR pathways remain relatively unaffected.
Several PARP inhibitors, including olaparib and niraparib, have clinical approval for treating ovarian, breast, pancreatic, and prostate cancers. Beyond PARP inhibitors, researchers explore targeting PARG, the enzyme responsible for PAR degradation. Inhibiting PARG leads to PAR chain accumulation, which can impair DNA repair and induce cancer cell death. PARG inhibitors are investigated as single agents or in combination with other cancer treatments, including PARP inhibitors, to enhance efficacy and overcome drug resistance.