DNA is often compared to a detailed instruction manual for the cell, containing the genetic information needed for it to function, grow, and divide. DNA damage is like a collection of typos or torn pages in that manual, altering the physical or chemical structure of the DNA molecule. These changes can garble the instructions, making them difficult for the cell to read correctly.
This damage is not a rare event but a constant cellular challenge. Each cell in the human body can experience thousands of molecular lesions daily. If the information in the genetic blueprint is altered, it can disrupt the cell’s ability to produce necessary proteins and carry out its functions properly.
External Factors Causing DNA Damage
Our DNA is exposed to damaging agents from the outside world. A common source is ultraviolet (UV) radiation from sunlight. When UV rays penetrate skin cells, they can cause adjacent pyrimidine bases—typically two thymines—to fuse, creating a bulky lesion known as a pyrimidine dimer. This kink in the DNA structure can block the machinery that reads and copies the genetic code.
Chemical mutagens from our environment and lifestyle choices also pose a significant threat. Compounds in tobacco smoke, for example, can attach to DNA bases, forming large, disruptive structures called DNA adducts. Other examples include aflatoxins, poisons produced by molds on food, and various industrial pollutants that can chemically alter DNA.
Another powerful external source of damage is ionizing radiation, including X-rays and gamma rays. This high-energy radiation can penetrate deep into the body and create highly reactive molecules. The primary danger is its ability to cause breaks in the DNA’s sugar-phosphate backbone. This can result in a single-strand break or a more severe double-strand break, where both strands are severed.
Internal Processes Leading to DNA Damage
Many sources of DNA damage arise from the body’s normal activities. The process of converting food into energy, known as metabolism, generates unstable byproducts called reactive oxygen species (ROS). These highly reactive molecules can attack DNA, causing chemical modifications. A common example is the conversion of guanine into 8-oxo-guanine, a lesion that can cause incorrect base pairing.
DNA replication, which occurs every time a cell divides, is another source of internal damage. The machinery that copies the genetic code is highly accurate but not perfect. Occasionally, an incorrect nucleotide is inserted, creating a mismatch. While cells have proofreading systems, some errors can slip through and become permanent.
The chemical bonds in DNA can also spontaneously break down in the warm, watery environment inside a cell. One process, spontaneous deamination, can cause the base cytosine to turn into uracil. Another, depurination, involves the loss of a purine base from the DNA backbone, leaving a gap. Thousands of these depurination events are estimated to occur in each cell daily.
The Body’s Natural Repair Mechanisms
Fortunately, cells are not defenseless against this constant damage. They possess a toolkit of proteins and enzymes that act as a cellular repair crew. This system patrols the genome, searching for chemical or structural abnormalities. When damage is detected, these proteins trigger signals to initiate repairs, ensuring the cell can function correctly.
This system uses different strategies depending on the problem. For simple errors like a single damaged base, base excision repair snips out the faulty base and replaces it. For more complex issues like the bulky dimers from UV light, nucleotide excision repair removes a segment of the damaged DNA strand, which is then re-synthesized using the intact strand as a template.
For the most dangerous damage, double-strand breaks, cells have two primary pathways. One is homologous recombination, which uses an undamaged section of a similar DNA molecule as a template to accurately fill in the gaps. The other pathway, non-homologous end joining, trims the broken ends and fuses them together. These mechanisms fix the vast majority of DNA lesions that occur daily.
Health Implications of Accumulated Damage
When the rate of DNA damage overwhelms the body’s repair capacity, or if repair mechanisms are faulty, the consequences can be significant. The accumulation of damage can lead to permanent changes in the DNA sequence, known as mutations. If these mutations occur in genes that regulate cell growth, they can cause cells to multiply uncontrollably, leading to cancer.
The steady accumulation of DNA damage is also a major contributor to the aging process. Over time, as damage builds up, cells may enter a state of irreversible growth arrest called cellular senescence or may die off. This gradual loss of functional cells contributes to the decline of tissue and organ function that characterizes aging.
Accumulated DNA damage in long-lived cells like neurons is linked to neurodegenerative diseases. Research suggests a connection between the buildup of DNA lesions in brain cells and conditions such as Alzheimer’s and Parkinson’s disease. The inability of neurons to effectively repair their DNA may lead to their progressive dysfunction and death, contributing to the disorders’ symptoms.