How a DNA Polymerase Protects Cells from DNA Damage

Researchers from Mount Sinai used advanced cryo-electron microscopy to reveal the three-dimensional structure and mechanism of DNA polymerase ζ (Pol ζ), which protects cells from constant DNA damage. Their study was published today in Nature Structural & Molecular Biology. 

"Resolving the structure of the complete Pol ζ enzyme at near-atomic resolution allows us to address long-standing questions of how this unique polymerase replicates through daily DNA-damaging events, while also providing a template for designing drugs against cancers that are refractory to conventional chemotherapeutics," says lead author Aneel Aggarwal.

DNA polymerase ζ is the crucial enzyme that allows cells to battle the more than 100,000 DNA-damaging events that occur daily from normal metabolic activities and environmental intrusions like ultraviolet light, ionizing radiation, and industrial carcinogens. According to  the team, the enzyme protects the cells from natural and manmade environmental as well cellular stresses through an intricate structure of four different proteins that connect to each other in a pentameric, or daisy chain-like, configuration.

This architecture is expected to provide valuable insights to scientists for the future development of drugs designed to inhibit the DNA polymerase when treating cancers like non-small-cell lung, prostate, and ovarian that often become resistant to chemotherapy after early use in patients. The reason for that resistance is that chemotherapies like cisplatin actually depend on their DNA-damaging effects. Thus, blocking or inhibiting the function of Pol ζ makes the cancerous cells more sensitive to the therapeutic impact of chemotherapy.

"The development of effective inhibitors has been hampered in the past by a lack of structural information on Pol ζ," explains Dr. Aggarwal. "Our work now offers a much clearer picture, and we expect these new insights will spur efforts by scientists around the world to create effective new therapies."