DNA is remarkably stable, but it is not chemically indestructible. Every cell in the body is exposed to conditions that can alter DNA, from normal chemical reactions during metabolism to ultraviolet radiation from sunlight. DNA can also be damaged by certain chemicals, radiation, replication errors, and by-products of inflammation.
DNA damage is therefore a normal part of life. What matters is what happens next. Cells constantly detect damaged DNA, repair many types of damage, and, when necessary, stop dividing or eliminate severely damaged cells. Problems arise when damage escapes repair or is copied into the genome before it can be corrected. Persistent changes can contribute to aging, cell malfunction, and cancer.
What does DNA damage mean?
DNA damage is a physical or chemical alteration to DNA that can interfere with its normal structure or function. Damage can affect one or both DNA strands and can range from a small chemical change to a break in the DNA backbone.
One common form is a base modification, in which one of DNA’s four chemical bases—adenine, thymine, cytosine, or guanine—is chemically altered. Other forms include missing bases, breaks in the DNA backbone, abnormal links between DNA strands, and bulky lesions that distort the DNA molecule.
DNA damage is different from a mutation. Damage is an abnormality in the DNA molecule itself. A mutation is a permanent change in the DNA sequence that remains after DNA has been copied or repaired. If damaged DNA is accurately repaired, no mutation results. If damage is copied incorrectly or repaired inaccurately, it can become a mutation.
Damage that happens inside the cell
A large amount of DNA damage comes from ordinary cellular activity rather than from an outside environmental exposure.
Reactive molecules produced during metabolism
Cells continually use oxygen and nutrients to produce energy and carry out other chemical reactions. Some of these reactions generate highly reactive molecules, including certain forms of oxygen and nitrogen.
These molecules can react with DNA and chemically modify its bases or damage the DNA backbone. For example, oxidation can alter guanine in a way that makes it more likely to pair incorrectly during DNA replication.
Cells normally control reactive molecules with antioxidant systems and other defenses, but these defenses are not perfect. Reactive molecules can also increase during inflammation and other forms of cellular stress.
Spontaneous chemical changes in DNA
DNA is constantly undergoing ordinary chemical reactions, even under normal physiological conditions. Water and other molecules in the cell can cause some DNA bases to change spontaneously.
One important example is deamination, a reaction in which a DNA base loses an amino group. Cytosine can undergo deamination and become uracil, a base normally associated with RNA rather than DNA. If the resulting mismatch is not corrected, it can eventually produce a permanent sequence change.
DNA bases can also be lost altogether through a process called depurination, leaving an empty site in the DNA strand.
These reactions occur naturally and are one reason cells need continuous DNA surveillance and repair.
Errors during DNA replication
Before a cell divides, it must copy its DNA. DNA-copying enzymes are highly accurate and have proofreading mechanisms, but they occasionally insert the wrong base or make other copying errors.
Most such errors are corrected by proofreading and additional repair systems. A small fraction can escape correction. If the cell subsequently copies the altered sequence, the error can become a mutation.
Replication can also be difficult when the DNA template contains existing damage. A replication machine may stall, bypass the damaged site in a way that introduces an error, or trigger specialized repair processes.
DNA damage from inflammation
Inflammation is a normal biological response to infection, injury, and other threats. Immune cells use chemically reactive substances as part of their defense mechanisms. Those substances can also react with nearby molecules, including DNA.
Short-term inflammation does not necessarily cause lasting genetic problems because cells have repair and protective systems. Persistent inflammation, however, can repeatedly expose tissues to conditions that promote DNA damage and cellular stress.
Damage from outside the cell
External sources can add substantially to the DNA damage a cell experiences. Some of the most important are forms of radiation and certain chemical exposures.
Ultraviolet radiation from sunlight
Ultraviolet, or UV, radiation can directly damage DNA in skin cells. UVB radiation is particularly effective at producing lesions in which neighboring pyrimidine bases, such as thymine, become abnormally linked.
These lesions distort the DNA structure and interfere with accurate copying. If they are not repaired correctly, they can contribute to mutations in skin cells.
UVA radiation can also contribute to DNA damage, in part by promoting the formation of reactive molecules that indirectly damage cellular components.
This is one reason excessive ultraviolet exposure increases the risk of skin cancer.
Ionizing radiation
Ionizing radiation has enough energy to remove electrons from atoms and molecules, producing ions and highly reactive chemical species. It includes forms such as X-rays and gamma rays.
Ionizing radiation can damage DNA directly or indirectly through reactive molecules generated from water and other cellular components. It can produce altered bases, single-strand breaks, and, more seriously, double-strand breaks, in which both strands of the DNA molecule are broken near the same location.
Double-strand breaks are particularly consequential because the cell must accurately reconnect the DNA or use another mechanism to restore the genetic information.
Chemicals that damage DNA
Some chemicals can react directly with DNA or be converted inside the body into compounds that can. These substances may attach chemical groups to DNA bases, alter their structure, or interfere with DNA replication.
Some environmental and occupational exposures contain chemicals capable of causing such damage. Tobacco smoke, for example, contains compounds that can form DNA adducts—chemical attachments to DNA that can interfere with accurate copying and repair.
The effects of a chemical exposure depend on the substance, the amount and duration of exposure, how the body metabolizes it, and the tissues involved.
Certain medical treatments
Some cancer treatments deliberately damage DNA because rapidly dividing cancer cells can be especially vulnerable to disruptions in DNA replication and repair. Radiation therapy and several types of chemotherapy work partly through this mechanism.
This illustrates an important point: DNA damage is not automatically harmful in every context. Controlled DNA damage can be therapeutically useful when it helps eliminate diseased cells. The challenge is limiting damage to healthy tissue while effectively targeting cancer cells.
What happens when DNA is damaged?
Cells do not simply leave damaged DNA in place. They have interconnected systems that detect problems, pause DNA replication or cell division when necessary, repair the DNA, and determine whether a damaged cell should survive.
Different types of damage require different repair mechanisms. Small chemically altered bases can often be removed and replaced. Bulky distortions may require a repair pathway that cuts out a short section of the damaged DNA and rebuilds it using the undamaged strand as a template.
When a single DNA strand is broken, the intact strand can often provide a guide for restoring the damaged strand. Double-strand breaks are more difficult because there is no intact strand spanning the entire break. Cells can repair these breaks by directly joining the ends or by using a matching DNA sequence as a template when one is available.
Repair is not always perfect. Some forms of damage are repaired accurately most of the time but can occasionally produce a permanent sequence change.
When DNA damage becomes a mutation
A damaged DNA molecule does not automatically mean that the cell’s genetic information has changed permanently.
Consider a DNA base that has been chemically altered. If the cell recognizes and replaces it before the DNA is copied, the original sequence can be restored. If the damage remains during replication, however, the replication machinery may interpret the altered base incorrectly. After another round of DNA copying, the change may become fixed in the genome.
Mutations can also result from inaccurate repair.
This distinction explains why the body can tolerate substantial amounts of DNA damage without every damaged cell becoming genetically abnormal. The repair systems are a major barrier between temporary molecular damage and permanent genetic change.
Why DNA damage matters for cancer
Cancer develops when cells acquire combinations of genetic changes that alter the controls governing growth, survival, and other cellular behaviors. DNA damage is one route by which those changes can arise.
The relationship is not simply that “DNA damage causes cancer.” Cells have multiple layers of protection: DNA repair, checkpoints that slow or stop cell division, and mechanisms that can eliminate cells that are too damaged to function safely.
Cancer risk increases when damaging exposures are substantial or repeated, when repair systems fail, or when mutations accumulate in genes that regulate cell growth and genome stability. Some people also inherit variants that make particular DNA-repair pathways less effective, increasing susceptibility to certain cancers.
DNA damage and aging
DNA damage also accumulates as organisms age, although aging is influenced by many interacting biological processes and cannot be reduced to DNA damage alone.
Cells continually repair DNA, but repair is not flawless. Some damage can persist, and cells may accumulate mutations over time. Other age-related changes affect how efficiently cells respond to DNA damage or maintain the integrity of their genomes.
At the same time, cells have mechanisms that limit the consequences of damaged DNA. A cell may enter a state in which it no longer divides, or it may undergo programmed cell death if its genetic damage is too extensive.
The body cannot prevent all DNA damage—and does not need to
DNA damage is unavoidable because it arises both from the chemistry of life and from environmental exposures. The goal of cellular defenses is therefore not to maintain DNA in a perfectly untouched state. Instead, cells continually monitor, repair, tolerate, or eliminate damage.
The most important distinction is between damage that is repaired and damage that becomes a lasting genetic change. Sunlight, radiation, reactive molecules, spontaneous chemical reactions, replication errors, and certain chemicals can all injure DNA. Sophisticated repair and surveillance systems normally correct much of that damage.
When those systems cannot keep up, when damage occurs in critical parts of the genome, or when repair introduces errors, DNA damage can have lasting biological consequences. That balance between constant molecular wear and remarkably effective repair is what allows cells to preserve genetic information over a lifetime.
