Cyclobutane pyrimidine dimers, often referred to as CPDs, are a type of DNA damage. They are primarily triggered by exposure to ultraviolet (UV) radiation, particularly the UV-B spectrum of sunlight. CPDs are a significant factor in the harmful effects observed in skin following sun exposure. Understanding these dimers helps explain how sunlight impacts our genetic material at a fundamental level.
Formation and Structure of Cyclobutane Pyrimidine Dimers
DNA is composed of four building blocks: adenine (A), guanine (G), cytosine (C), and thymine (T). Among these, cytosine and thymine are pyrimidines. When UV-B light strikes DNA, it can cause a chemical reaction between two pyrimidine bases that are positioned next to each other on the same DNA strand. This leads to the formation of new covalent bonds between these adjacent pyrimidines.
These new bonds create a four-membered cyclobutane ring, which links the two pyrimidine bases together. This distortion affects the DNA’s normal double helix shape, making it difficult for cellular machinery to read genetic information correctly. The most common CPDs involve two adjacent thymines (T-T dimer), but T-C, C-T, and C-C dimers can also form.
Cellular Repair Mechanisms
Cells have systems to detect and correct DNA damage, including cyclobutane pyrimidine dimers. One direct repair mechanism, photoreactivation, involves a specialized enzyme called photolyase. This enzyme uses energy from visible light to directly break the bonds of the cyclobutane ring, restoring the DNA to its undamaged state. Photoreactivation is a widespread repair pathway found in many organisms (e.g., bacteria, fungi, and plants), but it is notably absent in placental mammals, including humans.
Humans primarily rely on Nucleotide Excision Repair (NER) to address CPDs. NER operates as a “cut and patch” mechanism. First, specialized proteins recognize the distortion caused by the CPD within the DNA helix. These proteins recruit other enzymes that precisely cut out a segment of the DNA strand containing the damaged dimer. DNA polymerase then fills the resulting gap by synthesizing new DNA, using the undamaged opposite strand as a template. Finally, DNA ligase seals the new segment into the DNA backbone.
Impact on DNA Replication and Transcription
A cyclobutane pyrimidine dimer within a DNA strand poses a physical obstacle for the cellular machinery responsible for maintaining and utilizing genetic information. The distorted shape of the DNA helix at the site of a CPD can prevent enzymes from moving along the strand. This interference impacts two fundamental processes: DNA replication and transcription.
During DNA replication, DNA polymerase is responsible for accurately copying the entire genome before cell division. When DNA polymerase encounters a CPD, its progress can be hindered or halted. This stalling can interrupt the replication fork, preventing the cell from completing DNA synthesis. Similarly, RNA polymerase, which reads genes to create RNA molecules during transcription, also encounters difficulties. It can stall or terminate transcription when it encounters a CPD, preventing the proper expression of the affected gene.
Long-Term Health Consequences
When cellular repair mechanisms, particularly Nucleotide Excision Repair, fail to remove CPDs, cells may resort to alternative, often error-prone, strategies to continue DNA replication. One such process is translesion synthesis (TLS), where specialized DNA polymerases can bypass the damaged site. These TLS polymerases are less accurate than the primary replicative polymerases and may insert incorrect bases opposite the CPD. This leads to permanent changes in the DNA sequence, known as mutations.
A common mutation induced by CPDs, especially in the context of UV exposure, is a C-to-T transition, where a cytosine base is mistakenly replaced by a thymine. Accumulation of these mutations in specific genes can have severe health consequences. If mutations occur in genes that regulate cell growth, such as tumor suppressor genes, they can lead to uncontrolled cell proliferation. This uncontrolled growth is a hallmark of various skin cancers, including basal cell carcinoma, squamous cell carcinoma, and melanoma. Individuals with genetic disorders like Xeroderma Pigmentosum, who have defects in their NER pathway, exhibit extreme sensitivity to sunlight and face an elevated risk of developing these skin cancers at an early age.