Our bodies are made of countless cells, and within each cell lies deoxyribonucleic acid, or DNA, which serves as the fundamental instruction manual for all living things. This complex molecule holds the genetic information that guides how organisms grow, develop, function, and reproduce. The precise sequence of its building blocks, called nucleotides, dictates the production of proteins that carry out most cellular functions, from forming structural components to catalyzing biochemical reactions. However, this biological blueprint is constantly exposed to various factors that can cause damage, necessitating sophisticated repair mechanisms to maintain its integrity and ensure proper cellular function.
Sources and Types of DNA Damage
DNA faces continuous threats from both internal processes within the body and external environmental agents. Endogenous damage, originating from normal cellular activities, includes errors during DNA replication where incorrect bases might be inserted or small sections missed or duplicated. Metabolic byproducts, such as reactive oxygen species (ROS), also frequently cause oxidative damage to DNA bases, with estimates suggesting tens of thousands of such events per cell per day in humans. Spontaneous chemical reactions like hydrolysis can lead to the loss of DNA bases or the deamination of cytosine, changing it into uracil.
Exogenous factors from the environment also contribute to DNA damage. Ultraviolet (UV) radiation from the sun induces the formation of pyrimidine dimers where adjacent pyrimidine bases on the same DNA strand bond together. Ionizing radiation can cause breaks in DNA strands, including both single-strand breaks and more severe double-strand breaks. Chemical mutagens can also modify DNA bases or form bulky adducts, which are large chemical groups attached to the DNA, altering its structure.
The Body’s Repair Mechanisms
The human body possesses an intricate network of DNA repair pathways, each specialized to address different types of damage and maintain genomic stability. These mechanisms operate continuously to counteract the constant assault on DNA.
Nucleotide Excision Repair (NER) handles bulky DNA lesions that distort the DNA helix, such as those caused by UV radiation or certain chemical mutagens. A complex of proteins recognizes the distortion in the DNA structure. Specialized enzymes, known as excinucleases, cut the damaged DNA strand on both sides of the lesion, typically removing a segment of about 24-32 nucleotides in humans. The resulting gap is filled by a DNA polymerase using the undamaged complementary strand as a template, and DNA ligase seals the remaining nick to restore the DNA’s integrity.
For smaller, more subtle alterations to individual DNA bases, Base Excision Repair (BER) is the primary defense. This pathway begins with a DNA glycosylase enzyme identifying and removing the damaged or incorrect base, leaving behind an abasic site, also known as an AP site. An AP endonuclease then cleaves the DNA backbone at this site, and a DNA polymerase fills the single-nucleotide gap using the correct base. DNA ligase completes the repair by sealing the remaining break in the sugar-phosphate backbone.
When errors occur during DNA replication, such as mismatched base pairs or small insertions or deletions, the Mismatch Repair (MMR) system steps in. This pathway distinguishes the newly synthesized strand from the older, correct template strand. Specific proteins identify the mismatched base pair, and a segment of the newly synthesized DNA strand containing the error is excised. A DNA polymerase then synthesizes the correct sequence, and DNA ligase joins the newly synthesized patch to the existing strand.
For double-strand breaks (DSBs), where both strands of the DNA helix are severed, the cell employs two main repair pathways: Non-Homologous End Joining (NHEJ) and Homologous Recombination (HR). NHEJ directly ligates the broken ends of the DNA together. While efficient, this process can sometimes lead to small deletions or insertions at the repair site, as it does not rely on a template for perfect reconstruction.
Homologous Recombination (HR) is a more accurate repair pathway for double-strand breaks, especially active during the S and G2 phases of the cell cycle when a sister chromatid is available as a template. This mechanism uses the undamaged sister chromatid as a guide to precisely repair the broken DNA strand, ensuring no genetic information is lost. The broken ends are processed, and specialized proteins facilitate the invasion of the homologous DNA template, allowing for accurate repair.
Consequences of Impaired DNA Repair
When DNA repair mechanisms fail to correct damage, the consequences can affect cellular function and overall health. Unrepaired DNA lesions can lead to genomic instability, where the DNA sequence becomes altered or rearranged. These alterations, if replicated, can become permanent mutations, potentially changing gene function or regulation.
The accumulation of unrepaired DNA damage is linked to health issues, including aging. Cells with extensive DNA damage or impaired repair capabilities may enter a state of dormancy known as senescence, or undergo programmed cell death, called apoptosis. While these mechanisms can prevent the propagation of damaged cells, their widespread occurrence can contribute to tissue degeneration and age-related decline.
Impaired DNA repair increases susceptibility to cancer. Mutations in genes responsible for DNA repair pathways can lead to a higher rate of errors accumulating in the genome, increasing the likelihood of mutations in genes that control cell growth and division. For instance, individuals with inherited mutations in the BRCA1 and BRCA2 genes, which are involved in homologous recombination repair of double-strand breaks, have an elevated risk of developing breast, ovarian, and other cancers. The inability to properly fix DNA damage allows cancerous cells to proliferate uncontrollably, evade the immune system, and develop drug resistance.