Thymine dimers are a form of genetic damage resulting from the DNA molecule absorbing high-energy light, primarily ultraviolet (UV) radiation. They are abnormal covalent bonds formed between adjacent molecular building blocks within a single strand. Specifically, a thymine dimer is a type of cyclobutane pyrimidine dimer (CPD), where two neighboring thymine bases become chemically linked. The cell’s ability to recognize and repair these lesions is required for maintaining genomic stability.
How Ultraviolet Light Causes Dimer Formation
The formation of a thymine dimer begins when DNA absorbs energy from specific wavelengths of ultraviolet light. Both UV-B (280 to 320 nanometers) and the more energetic UV-C radiation (200 to 280 nm) are readily absorbed by the pyrimidine bases in DNA. Since DNA has maximum absorption around 260 nanometers, it efficiently captures energy from these UV bands.
This absorbed energy excites the electrons within the thymine molecules, making them chemically reactive. If two thymine bases are positioned next to each other on the same DNA strand, the excitation triggers a photochemical reaction. This reaction forms a four-carbon cyclobutane ring, creating a new covalent bond that links the two adjacent bases. This bond fuses the neighboring thymines into a single, damaged unit.
The Physical Impact on DNA Structure
The introduction of this covalent bond alters the local geometry of the DNA double helix. The cyclobutane ring locks the two thymine bases into a fixed position, preventing the smooth spiral of the backbone from continuing. This localized structural defect creates a “kink” or “bulge” in the DNA strand.
The dimer can cause the DNA helix to bend significantly, with distortion angles ranging from 10 to 30 degrees. This bending prevents the damaged thymines from properly engaging with complementary adenine bases on the opposing strand. Consequently, the hydrogen bonds holding the two strands together in that region are weakened or broken, disrupting the uniform structure necessary for DNA function.
Disrupting Replication and Transcription
This physical distortion transforms the genetic code into a roadblock for the cellular machinery that reads it. During DNA replication, DNA Polymerase stalls when it encounters the thymine dimer. The active site of the polymerase cannot accommodate the distorted shape, causing the replication fork to stop moving forward.
Similarly, during gene expression, RNA Polymerase, which transcribes DNA into messenger RNA, also encounters the dimer as an impassable barrier and stalls. When the cell attempts to bypass this roadblock using specialized, error-prone enzymes in a process called translesion synthesis, the chance of mutation increases dramatically. These bypass polymerases often misincorporate an incorrect base opposite the dimer, leading to a permanent point mutation in the DNA sequence.
Unrepaired dimers or the resulting mutations can trigger cellular consequences. If the damage is extensive, the cell may activate a programmed cell death pathway known as apoptosis to prevent the damaged DNA from being passed on. However, if the damaged DNA is copied with errors and the mutations affect genes that control cell growth, this can initiate the process of carcinogenesis, ultimately leading to cancer.
Cellular Strategies for DNA Repair
To combat the threat from UV light, human cells use Nucleotide Excision Repair (NER). NER is a pathway designed to recognize and remove lesions that distort the DNA helix, with thymine dimers being a primary target. The process begins with specialized protein complexes recognizing the structural distortion caused by the dimer.
Once recognized, a multi-protein complex opens the DNA helix around the damage site. Endonuclease enzymes make two precise cuts in the damaged strand, excising a segment of about 25 to 30 nucleotides. The resulting gap is filled by a DNA polymerase using the intact complementary strand as a template. Finally, DNA ligase seals the remaining nick, restoring the DNA to its original sequence. The importance of NER is highlighted by genetic conditions like Xeroderma Pigmentosum, where defects in this pathway lead to increased susceptibility to UV-induced skin cancers.