Pyrimidine dimers are a form of DNA damage where two adjacent pyrimidine bases on the same DNA strand become linked. These bases, usually cytosine or thymine, form covalent bonds. This structural alteration disrupts the normal double helix of DNA. They impact cellular function and genetic integrity.
How Pyrimidine Dimers Form
Pyrimidine dimers form due to exposure to ultraviolet (UV) radiation, particularly UV-B and UV-C light. When UV photons are absorbed by adjacent pyrimidine bases, they gain energy, leading to a photochemical reaction. This causes the bases to bond atypically.
New covalent bonds form between the carbon atoms of neighboring pyrimidine bases. The most common types are cyclobutane pyrimidine dimers (CPDs), where a four-membered cyclobutane ring forms between the C5 and C6 atoms of two adjacent pyrimidines. Another type, the (6-4) photoproduct, involves a bond between the C6 of one pyrimidine and the C4 of the adjacent one. This abnormal bonding distorts the DNA double helix, preventing the bases from pairing correctly with their counterparts on the opposite strand.
Impact on DNA and Cells
The distorted DNA structure interferes with cellular processes. During DNA replication, DNA polymerases encounter the dimer and may stall or insert incorrect bases opposite the damaged site. This impediment can lead to errors in the newly synthesized DNA strand.
Similarly, during transcription, the process where DNA is used as a template to create RNA, RNA polymerase can be hindered by the dimer, preventing accurate gene expression. If these disruptions are not corrected, the errors introduced during replication can become permanent mutations in the cell’s genome. These mutations can alter gene function, potentially leading to uncontrolled cell growth.
Unrepaired pyrimidine dimers are linked to skin cancers, including melanoma and non-melanoma types. The accumulation of these mutations can initiate or promote the cancerous transformation of cells. In cases of extensive and unrepaired DNA damage, cells have a protective mechanism known as programmed cell death, or apoptosis, which eliminates severely damaged cells to prevent their proliferation.
Cellular Repair Mechanisms
Cells have mechanisms to repair pyrimidine dimer damage, maintaining genomic stability. One primary pathway in humans is Nucleotide Excision Repair (NER). This multi-step process begins with the recognition of the bulky distortion in the DNA helix caused by the dimer.
Once recognized, a segment of the damaged DNA strand, typically 24-32 nucleotides long and containing the dimer, is excised by specialized enzymes. Following the removal of the damaged section, DNA polymerase synthesizes a new, correct segment of DNA using the undamaged complementary strand as a template. Finally, DNA ligase seals the newly synthesized DNA into the existing strand, restoring the DNA’s original integrity.
Another repair mechanism, known as photoreactivation or direct repair, is found in many organisms but is not a direct repair pathway in placental mammals, including humans. In organisms that utilize it, enzymes called photolyases can directly reverse the cyclobutane pyrimidine dimer formation. These enzymes absorb energy from visible light to break the covalent bonds within the dimer, directly restoring the original pyrimidine bases without removing any DNA. These repair systems safeguard the genome from UV radiation, preventing diseases associated with DNA damage.