Within every living cell, a constant effort is underway to maintain the integrity of the genetic blueprint, DNA. An important participant in this process is the enzyme DNA polymerase beta (Pol β). Discovered in 1971, this enzyme acts as a first responder to specific kinds of DNA damage, helping to correct errors that can arise in the genetic code.
Pol β is tasked with a very specific form of repair. Its role is not to replicate entire strands of DNA, which is handled by other types of polymerases, but rather to perform small, detailed corrections. This function is important for upholding the stability of the genome and ensuring the genetic instruction manual remains accurate.
The Role of DNA Polymerase Beta in Base Excision Repair
DNA is constantly exposed to damaging agents from the environment and from processes within our cells. These sources can cause chemical alterations to the individual bases of DNA. A primary pathway for fixing this small-scale damage is called Base Excision Repair (BER), which identifies and corrects single-base errors.
The BER process is a multi-step operation involving several different enzymes. The process begins when an enzyme called a DNA glycosylase discovers and removes a damaged base. This action leaves behind a gap in the DNA strand, at which point Pol β is recruited to the site of the damage.
Pol β’s function within the BER pathway is to fill the single-nucleotide gap left after the damaged base has been excised. It carefully selects the correct DNA nucleotide from the cellular pool and inserts it into the empty space, ensuring the genetic sequence is restored to its original state. This gap-filling activity is a central part of the repair process.
The Two-Step Mechanism of DNA Polymerase Beta
Pol β accomplishes its repair function through a two-step enzymatic mechanism contained within its structure. Its two main domains work in a coordinated sequence to first insert a new DNA base and then clean up the remaining debris from the damaged site.
The first action is its DNA polymerase activity. After a damaged base is removed, Pol β binds to the gapped DNA and reads the opposing, undamaged strand to determine which of the four DNA nucleotides (A, T, C, or G) is correct. Once the correct nucleotide is identified, the polymerase function of Pol β chemically links it into the vacant spot in the DNA backbone.
After inserting the new nucleotide, a chemical remnant of the original damaged base, known as a 5′-deoxyribose phosphate (dRP) group, remains. This debris must be removed, which is the second function of Pol β: its dRP lyase activity. The lyase function acts like a pair of molecular scissors, snipping off the dRP fragment and clearing the way for another enzyme, DNA ligase, to seal the nick in the DNA backbone and fully restore the integrity of the strand.
Consequences of DNA Polymerase Beta Dysfunction
When DNA polymerase beta does not function correctly, errors in the Base Excision Repair pathway can lead to the accumulation of DNA damage. This can cause mutations to become a permanent part of the genetic code. A deficient or structurally variant Pol β may fail to fill gaps efficiently or may insert the wrong nucleotide into a repair site.
This faulty repair activity can lead to genomic instability, a state where the genome is more likely to undergo changes. This instability is a known characteristic of many types of cancer. Studies have shown that some tumor-associated versions of Pol β can catalyze faulty repair, which suggests that a properly functioning enzyme acts as a tumor suppressor by maintaining genomic stability.
Beyond cancer, Pol β dysfunction has other health implications. The accumulation of unrepaired DNA damage is a factor in the aging process. Research has also pointed to a link between problems in DNA repair pathways and certain neurodegenerative disorders.
Targeting DNA Polymerase Beta in Cancer Therapy
While a faulty Pol β can contribute to cancer, its normal function presents a challenge in cancer treatment. Many standard cancer therapies, including chemotherapy and radiation, work by inflicting extensive DNA damage on rapidly dividing cancer cells. The goal is to damage the cells so severely that they can no longer replicate and are forced to self-destruct.
Cancer cells, however, can use their own DNA repair machinery, including the BER pathway, to survive these treatments. By using Pol β to mend the damage caused by therapy, the cells can develop treatment resistance. An effective repair ability makes a cancer cell more likely to survive and multiply, leading to disease recurrence.
This has led researchers to develop a therapeutic strategy that targets Pol β directly with drugs known as Pol β inhibitors. These molecules block the enzyme’s function, preventing cancer cells from repairing the DNA damage inflicted by chemotherapy. This makes the primary cancer treatment more potent, leaving the cancer cells vulnerable and increasing the likelihood of their elimination.