cyclobutane pyrimidine dimer (CPD) repair

CPD formation The most common and lethal damage caused to DNA through exposure to ultraviolet radiation is the formation of bonds between two pyrimidine bases to form a cyclobutane pyrimidine dimer (CPD). Unfortunately, CPD units, which lead to diseases like skin cancer, are quite stable at room temperature.

CPD in DNAA more realistic picture of DNA with a CPD lesion is shown to the left. Many organisms, including some vertebrates (but not humans), posses an enzyme, photolyase, which acts to repair CPD lesions. Photolyase is activated by absorption of a photon, which in turn triggers the transfer of an electron to the CPD site. While CPD units are very stable, the CPD anion comparatively rapidly separates into two normal pyrimidine bases. This offers exciting routes to the prevention of skin cancer. (We don't endorse such products, but you can even buy sunscreen that contains photolyase.) Naturally, this has generated an enormous amount of interest in understanding the mechanism of CPD repair.

A significant amount of effort has gone into the study of the repair of model compounds in solution. Foregoing the complexity of the enzyme for the moment, we have theoretically studied the splitting of a thymine CPD anion in water. Because the reaction involves chemical bond breaking, we employed ab initio molecular dynamics simulations to study the reaction. One result of our studies was a reaction free energy surface for the splitting of the dimer. The surface shows how the C5-C5' bond splits before the C6-C6' bond.

CPD free energy
surface

One of the missing puzzle pieces has been the timing of back electron transfer in the repair of the CPD anion. The anion has to give up its electron at some point to complete the repair. However, if it gives it up too soon, the system reverts to the stable, neutral CPD. We have proposed a simple model to explain how the timing of back electron transfer depends on the solvent environment.

This research was supported by the National Institutes of Health.

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