Deoxyribonucleic acid, commonly known as DNA, serves as the fundamental blueprint for all known life forms, containing the genetic instructions necessary for development, functioning, growth, and reproduction. Despite its structured nature, DNA is constantly susceptible to damage from various environmental factors. Among the many types of DNA damage, DNA dimers represent a common and significant form of molecular lesion. Understanding how these dimers form, the cellular disruption they cause, and the body’s repair mechanisms is important for their biological and health implications.
How DNA Dimers Form
The primary environmental trigger for DNA dimer formation is exposure to ultraviolet (UV) radiation, predominantly from sunlight. When UV light penetrates skin cells, its energy can be absorbed by adjacent pyrimidine bases on a single DNA strand, such as thymine or cytosine. This absorption causes these neighboring bases to form abnormal covalent bonds, creating two main types of DNA lesions: cyclobutane pyrimidine dimers (CPDs) and 6-4 pyrimidine-pyrimidone photoproducts (6-4 PPs). CPDs, characterized by a four-carbon ring structure, are the most frequently formed type of dimer. Skin cells can form approximately 50 to 100 such dimers every second when exposed to sunlight.
Disruption to Cellular Function
Once formed, DNA dimers introduce significant distortions into the DNA double helix structure, with cyclobutane pyrimidine dimers causing a bend of about 7 to 9 degrees in the DNA backbone, and 6-4 photoproducts inducing an even greater helical distortion. This physical alteration creates a bulky block that interferes with cellular processes. Such distortions hinder DNA replication, as DNA polymerase enzymes struggle to read past the damaged site. They can also obstruct DNA transcription. These interferences can lead to replication stalling, errors in nucleotide incorporation, and ultimately, cellular dysfunction or even cell death.
The Body’s Defense: DNA Repair Pathways
Living organisms possess mechanisms to counteract DNA damage, with Nucleotide Excision Repair (NER) being the primary pathway in humans for addressing DNA dimers. This multi-step process begins with the recognition of the bulky dimer by protein complexes like XPC-Rad23B, which scan the genome for distortions. Once identified, the DNA is unwound around the damaged site by the helicase activity of TFIIH, creating an open bubble.
Following this unwinding, two nucleases, XPF and XPG, make precise cuts on the damaged DNA strand: XPF incises approximately 20-25 nucleotides upstream (5′) of the lesion, and XPG cuts about 3-10 nucleotides downstream (3′). This dual incision removes a short, single-stranded oligonucleotide segment that contains the dimer.
The remaining gap in the DNA strand is then accurately filled in by DNA polymerase using the intact complementary strand as a template. Finally, DNA ligase seals the newly synthesized segment into the DNA backbone, restoring the original, undamaged sequence and maintaining genomic integrity.
Consequences of Unrepaired Dimers
If DNA dimers are not effectively repaired, they can lead to permanent changes in the DNA sequence, known as mutations, particularly during DNA replication. When DNA polymerase encounters an unrepaired dimer, it may insert incorrect nucleotides opposite the lesion, or the replication fork might stall or collapse. A common mutation associated with UV exposure is the C to T transversion, or even CC to TT double base substitutions, especially at dipyrimidine sites.
Unrepaired dimers can also contribute to broader genomic instability, potentially resulting in chromosomal rearrangements. These accumulating mutations increase the risk of developing skin cancers, including melanoma, basal cell carcinoma, and squamous cell carcinoma. Cells with unrepaired damage may also activate protective measures such as cell cycle arrest, pausing division to allow more time for repair, or apoptosis to prevent proliferation of damaged cells.