How Pyrimidine Dimers Form
Deoxyribonucleic acid (DNA) is the blueprint for all cellular functions. However, this molecule is constantly susceptible to damage from internal cellular processes and external environmental factors. Among DNA alterations, pyrimidine dimers are a significant form of damage that can disrupt the genetic code.
These dimers involve abnormal chemical bonds between adjacent pyrimidine bases on the same DNA strand. They typically involve thymine-thymine (T-T), cytosine-cytosine (C-C), or thymine-cytosine (T-C) pairings. The primary cause of pyrimidine dimer formation is exposure to ultraviolet (UV) radiation, such as from sunlight or tanning beds.
When UV radiation, particularly UVB, penetrates skin cells, its energy is absorbed by DNA bases. This causes a photochemical reaction, leading to the covalent linking of two adjacent pyrimidine bases. The formation of these dimers distorts the DNA double helix, creating a bulge or kink. This abnormality can impede the accurate reading and copying of genetic information.
The Body’s DNA Repair System
Cells possess sophisticated mechanisms to detect and correct DNA damage, including pyrimidine dimers. These DNA repair systems are continuously active, maintaining the integrity of the genome. Without them, DNA damage accumulation would quickly become incompatible with life.
The most prominent repair pathway for pyrimidine dimers is Nucleotide Excision Repair (NER). This multi-step process recognizes the distorted DNA structure caused by the dimer. Specialized proteins within the NER pathway scan the DNA, identifying these structural irregularities.
Once a pyrimidine dimer is identified, a complex of proteins cuts the damaged DNA strand on both sides of the lesion. This excision removes a short segment of the DNA strand, which includes the dimer. This leaves a gap in the DNA helix.
Following excision, a DNA polymerase synthesizes a new, correct DNA segment to fill the gap. This uses the undamaged complementary DNA strand as a template, ensuring accurate restoration of genetic information. Finally, a DNA ligase seals the newly synthesized segment into the DNA backbone, completing the repair. This process is crucial for preventing the harmful consequences of DNA damage.
When Repair Fails: Consequences of Unrepaired Dimers
While DNA repair systems are efficient, they are not infallible. If pyrimidine dimers are not repaired, they pose a significant threat during DNA replication. When a cell prepares to divide, its genome must be accurately duplicated. Unrepaired dimers present a physical block and a miscoding lesion for the DNA replication machinery.
The DNA polymerase, responsible for synthesizing new DNA strands, often struggles to accurately read past a distorted DNA template containing a dimer. This can lead to the insertion of incorrect bases opposite the dimer, or cause the polymerase to skip bases entirely. These errors result in permanent changes to the DNA sequence, known as mutations.
These mutations can manifest as point mutations (a single DNA base altered) or larger deletions or insertions. While some are harmless, others can have profound consequences. The location and type of mutation determine its potential impact. Unrepaired dimers, therefore, act as direct precursors to these genomic alterations.
Connecting Dimers to Cancer Development
The accumulation of unrepaired pyrimidine dimers and resulting mutations can contribute to cancer. This occurs when mutations affect genes that regulate cell growth, division, and death. Cells with unrepaired DNA damage may continue to divide, passing these genetic errors to daughter cells.
Proto-oncogenes are a group of genes susceptible to these mutations. They normally promote cell growth and division in a controlled manner. A mutation caused by an unrepaired pyrimidine dimer can transform a proto-oncogene into an oncogene, driving uncontrolled cell proliferation and an abnormal increase in cell numbers.
Tumor suppressor genes act as brakes on cell growth and division, preventing uncontrolled expansion. Mutations in these genes, often caused by unrepaired UV-induced damage, can inactivate them. The p53 tumor suppressor gene, frequently mutated in skin cancers, is a key example due to its role in responding to DNA damage. When p53 is inactivated, cells lose a mechanism for halting division or initiating programmed cell death.
The progressive accumulation of such mutations in both proto-oncogenes and tumor suppressor genes disrupts cell cycle control. This allows cells to grow and divide without proper regulation, leading to tumor formation. These uncontrolled cellular growths can become malignant, signifying cancer development, particularly skin cancers like melanoma and non-melanoma types, directly linking UV exposure, pyrimidine dimers, and compromised repair to disease onset.