A pyrimidine dimer is a form of DNA damage where two adjacent pyrimidine bases, such as thymine or cytosine, form an unwanted bond. This bonding is caused by exposure to ultraviolet (UV) light and represents a threat to a cell’s health and function. The formation of these dimers disrupts the DNA helix’s structure, leading to significant problems if not corrected.
How Pyrimidine Dimers Form
When DNA absorbs energy from UVB radiation in sunlight, it can trigger a photochemical reaction between two neighboring pyrimidine bases on the same strand. This energy causes covalent bonds to form between the bases, linking them into an abnormal structure. The most common types of these lesions are cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts.
This fusion creates a rigid, bulky lesion in the DNA strand, similar to two train cars being incorrectly welded together. Skin cells are especially vulnerable; exposure to sunlight can cause 50 to 100 of these reactions every second in a single cell.
The Impact on DNA Replication and Transcription
A pyrimidine dimer introduces a structural distortion into the DNA double helix. This lesion creates a bend or “kink” of about 30 degrees in the DNA, which physically obstructs the molecular machinery responsible for reading the genetic code. The smooth pathway that enzymes follow along the DNA strand is blocked by this malformation.
Two cellular processes are halted by this physical barrier: DNA replication and transcription. During replication, the enzyme DNA polymerase cannot move past the lesion to accurately copy the DNA sequence for cell division. Similarly, RNA polymerase, which reads DNA to create RNA for protein production, is also blocked. This blockage prevents the cell from dividing or producing the proteins necessary for its survival. If the cell attempts to replicate past the damage, the process can lead to single-strand or double-strand breaks in the DNA, escalating the genetic injury.
Natural DNA Repair Mechanisms
To counteract DNA damage, human cells possess a repair system known as Nucleotide Excision Repair (NER). This pathway acts as a “cut-and-patch” mechanism to fix the distortions caused by pyrimidine dimers. The NER process has two sub-pathways: global genomic repair (GG-NER), which scans the entire genome, and transcription-coupled repair (TC-NER), which targets lesions blocking active transcription.
The process begins when specialized proteins scan the DNA and recognize the structural kink from the dimer. Once identified, other proteins are recruited. A helicase complex unwinds the DNA around the lesion, creating a bubble-like opening.
This opening allows enzymes called endonucleases to act like molecular scissors, cutting the damaged strand on both sides of the dimer. This removes a segment of DNA about 30 nucleotides long containing the dimer. The gap is then filled by DNA polymerase using the undamaged strand as a template. Finally, DNA ligase seals the new piece into the DNA backbone, completing the repair.
The Link Between Unrepaired Dimers and Disease
Although the Nucleotide Excision Repair system is efficient, it is not perfect. When the system is overwhelmed by excessive UV exposure or is defective, pyrimidine dimers can persist in the DNA. If a cell attempts to replicate its DNA with an unrepaired dimer, it may use a “last-resort” mechanism called Translesion Synthesis (TLS). This process uses specialized, low-fidelity DNA polymerases to replicate past the damaged site.
While TLS allows replication to continue, it often comes at the cost of accuracy. These specialized polymerases are prone to inserting incorrect bases opposite the dimer, leading to a permanent change in the DNA sequence, known as a mutation. The accumulation of mutations in genes that regulate cell growth can cause cells to divide uncontrollably, a foundational characteristic of cancer.
This link between unrepaired UV damage and mutation is why prolonged sun exposure is a primary cause of skin cancers like basal cell carcinoma, squamous cell carcinoma, and melanoma. The connection is illustrated by the rare genetic disorder Xeroderma Pigmentosum (XP). Individuals with XP have mutations in the genes for the NER pathway, leaving them unable to effectively repair pyrimidine dimers. As a result, they exhibit extreme sensitivity to sunlight and face an increased risk of developing skin cancer at an early age.