Deoxyribonucleic acid (DNA) serves as the instruction manual for every cell. This complex molecule is constantly under threat from environmental factors, and one common form of damage is the pyrimidine dimer. This lesion forms primarily when cells are exposed to ultraviolet (UV) radiation, such as from sunlight. Pyrimidine dimers represent an abnormal chemical link between adjacent bases on the same DNA strand. The formation of these lesions challenges the integrity of the human genome and drives significant health risks.
How Ultraviolet Light Creates the Damage
Ultraviolet light possesses enough energy to directly alter the chemical structure of DNA bases. The pyrimidine bases, specifically cytosine and thymine, are particularly susceptible to this photochemical reaction. When two adjacent pyrimidine bases are on the same DNA strand, UV radiation induces them to form a covalent bond. This abnormal linkage creates a pyrimidine dimer.
The most frequent type is the cyclobutane pyrimidine dimer (CPD). UV-B and UV-C wavelengths are the most damaging, causing these adjacent bases to fuse together instead of properly pairing with a base on the opposite strand. In skin cells exposed to sunlight, hundreds of these dimerization reactions can occur every second. A less frequent but highly mutagenic form is the 6–4 photoproduct (6–4 PP), which involves a different covalent linkage.
Disruption of Cellular Processes
The core danger of a pyrimidine dimer lies in its ability to physically distort the DNA helix. The abnormal covalent bond causes a distinct kink in the DNA structure, disrupting the smooth double-helix shape. This physical alteration blocks the machinery that must read and copy the genetic code.
During DNA replication, DNA polymerase, the enzyme responsible for copying the genome, stalls when it encounters this structural deformation. This stalling prevents the cell from accurately and completely duplicating its genome, which is necessary for cell division. The cell’s ability to create proteins is also compromised, as the physical distortion blocks the progression of RNA polymerase during transcription. These lesions are cytotoxic, meaning they can directly lead to cell death.
The Body’s Specialized Repair Machinery
To counter this threat, the human body relies on Nucleotide Excision Repair (NER). NER is the primary mechanism in humans for removing pyrimidine dimers and other bulky DNA lesions. The process begins with specialized protein complexes that constantly scan the genome for distortions.
The NER Process
Once the damage is recognized, a group of proteins, including the transcription factor TFIIH, unwinds the DNA helix around the lesion to create an open bubble. Two separate incisions are then made in the damaged strand, one on the 3′ side and one on the 5′ side of the dimer. This dual incision releases a short segment of the DNA strand, typically 24 to 32 nucleotides long, which contains the entire pyrimidine dimer.
The resulting gap in the DNA is then filled in by a DNA polymerase enzyme using the undamaged, complementary strand as a template. Finally, a DNA ligase seals the newly synthesized patch into the backbone of the original strand, completing the repair. NER removes hundreds of thousands of pyrimidine dimers from the genome within a day following sun exposure.
Linking Dimers to Disease
When the NER mechanism is overwhelmed by excessive UV exposure or when it malfunctions due to genetic defects, the consequences can be severe. One major outcome is mutagenesis, which occurs if the cell attempts to bypass the dimer roadblock during replication. Specialized, error-prone DNA polymerases may insert incorrect bases opposite the dimer, leading to permanent changes in the genetic sequence.
These mutations often take the form of cytosine-to-thymine or CC-to-TT transitions at the site of the dimer, which is a characteristic “UV signature” of DNA damage. If these mutations occur in genes that control cell growth or division, such as tumor suppressor genes, the cell can become cancerous. This direct link establishes pyrimidine dimers as a major initiating event in the development of skin cancers, including both melanoma and non-melanoma types.
If the DNA damage is too widespread or the cell recognizes the lesion as irreparable, it may trigger apoptosis, or programmed cell death. This self-destruction is a protective mechanism to prevent the damaged genetic material from being passed on to daughter cells. The importance of the NER pathway is illustrated by the rare genetic disorder Xeroderma Pigmentosum (XP). Individuals with XP have defects in NER genes, leading to an extremely high risk of developing skin cancer at a young age.