Deoxyribonucleic acid, or DNA, serves as the instruction manual for all known life forms. This molecule contains the genetic information that guides an organism’s development, function, and reproduction. Organized into a double helix, DNA’s two linked strands resemble a twisted ladder. Alternating sugar and phosphate groups form the backbone, and four nitrogenous bases (adenine, cytosine, guanine, and thymine) connect the strands. This structure allows DNA to store vast amounts of biological information.
Though DNA is stable, it is constantly exposed to factors that can cause damage. Cells possess repair systems that maintain the integrity of this genetic information. These cellular defense mechanisms are continuously active, addressing various forms of damage.
Why DNA Needs Repair
DNA faces a continuous barrage of damaging agents, originating from both within the cell and its external environment. Internal factors (endogenous sources) arise from normal cellular processes. For instance, metabolic byproducts like reactive oxygen species (ROS) can chemically alter DNA bases. Errors also occur during DNA replication, leading to incorrect nucleotide insertions or small omissions. Spontaneous chemical changes, such as the deamination of cytosine to uracil, also contribute to internal DNA damage.
External factors (exogenous sources) are environmental agents that can harm DNA. Ultraviolet (UV) radiation from sunlight induces the formation of pyrimidine dimers that distort the DNA helix. Ionizing radiation, such as X-rays and gamma rays, can cause severe damage, including double-strand breaks. Chemical mutagens, found in pollutants or tobacco smoke, can also bind to DNA, forming bulky adducts that interfere with normal cellular processes.
Unrepaired DNA damage can lead to significant problems for a cell. Such damage can result in mutations, which are permanent changes in the DNA sequence that may disrupt gene function or alter protein production. If these errors accumulate, they can impede cellular processes like DNA replication and cell division, potentially affecting cell function or survival.
How Cells Fix DNA Damage
Cells employ a variety of specialized pathways to detect and correct different types of DNA damage.
Base Excision Repair (BER)
BER primarily addresses small, non-bulky lesions affecting a single DNA base, such as oxidized, alkylated, or deaminated bases. This pathway involves specific enzymes that first remove the damaged base. Then, the sugar-phosphate backbone is cleaved, and a new, correct nucleotide is inserted and ligated into place.
Nucleotide Excision Repair (NER)
NER removes larger, helix-distorting lesions. This system is effective against damage caused by UV radiation, like pyrimidine dimers, and bulky chemical adducts. NER recognizes the distortion, excises a segment of the damaged strand, and then synthesizes a new, correct DNA segment using the undamaged strand as a template.
Mismatch Repair (MMR)
MMR focuses on correcting errors that arise during DNA replication. Even with high fidelity DNA polymerases, occasional incorrect nucleotides are inserted, or small insertions or deletions occur. The MMR system identifies these mismatched base pairs or small loops, excises the erroneous segment from the newly synthesized strand, and then resynthesizes the correct sequence. This pathway significantly reduces the mutation rate, maintaining the accuracy of genetic information.
Double-Strand Break (DSB) Repair
For severe damage, such as breaks in both strands of the DNA helix, cells utilize DSB Repair pathways.
Non-Homologous End Joining (NHEJ)
One method is Non-Homologous End Joining (NHEJ), a direct repair mechanism. NHEJ ligates the broken DNA ends together, often leading to a small loss or gain of genetic information at the repair site. This pathway is active throughout the cell cycle and is a rapid response to prevent chromosome fragmentation.
Homologous Recombination (HR)
Alternatively, Homologous Recombination (HR) offers a more accurate method for repairing double-strand breaks. HR utilizes a homologous DNA template, typically the sister chromatid available after DNA replication, to precisely repair the break without loss of genetic information. This pathway is active during the S and G2 phases of the cell cycle when a sister chromatid is present, ensuring high-fidelity repair.
When Repair Pathways Go Wrong
When DNA repair pathways are defective or overwhelmed, cellular health is impacted. A compromised repair system leads to genomic instability, characterized by an accumulation of mutations and chromosomal abnormalities. This instability means the cell’s genetic blueprint becomes erratic.
Persistent DNA damage coupled with impaired repair mechanisms contribute to various health issues. Faulty DNA repair links to an increased susceptibility to conditions such as cancer development, where uncontrolled cell growth can arise from accumulated genetic errors. Inadequate DNA repair can also contribute to accelerated aging, as cellular function declines due to accumulating unrepaired damage over time.
Cells with unrepaired DNA damage often face specific fates to prevent the propagation of faulty genetic material. Such cells may undergo programmed cell death, known as apoptosis, effectively removing them from the population. Alternatively, they might enter senescence, a state where they permanently stop dividing, which can impact tissue function and contribute to age-related decline. Proper functioning of these repair pathways is important for maintaining cellular health and preventing disease progression.