DNA Damage: What It Is, Types, Symptoms, and Causes Explained

Deoxyribonucleic acid (DNA) is a giant molecule neatly packed inside the nucleus of each eukaryotic cell. It carries all the genetic information needed for protein synthesis, cell cycle progression, and proper cellular function.

DNA is made up of four chemical bases: adenine (A), cytosine(C), guanine (G), and thymine (T). These bases pair up (A with T and C with G) to form the complementary base pairs that stabilize the DNA double helix. The sequence of these base pairs encode genetic information for building proteins involved in regulating cell function. This arrangement is essential for the optimal function of the DNA, but alterations, also known as mutations,can lead to DNA damage and cause potential harm to the body.

In this article, we will learn about DNA damage, how it affects the body, the different types of DNA lesions that can occur, and their potential impact on your health.

What is DNA Damage?

Your DNA is like a blueprint or set of instructions written in code. If any part of that code is altered (changed, broken, or deleted), the cell may find it difficult to read the code correctly resulting in damage.

According to ScienceDirect, DNA damage refers to any alteration in the coding properties or genetic material that disrupts its ability to accurately transcribe or replicate. Such damage to the DNA has the potential to cause cell loss, chromosomal instability, mutagenic transformation of healthy cells, and diseases such as cancer.

Reactive molecules generated from metabolism or the environment oxidize DNA bases, cause strand breaks, and trigger alkylation or hydrolysis of bases. Ultimately, this compromises genomic integrity inducing cell death.

Fortunately, cells possess sophisticated repair mechanisms such as non-homologous end joining, homologous recombination, and poly(ADP-ribose) polymerase (PARP) that correct these lesions and restore DNA integrity.

How DNA Damage Affects the Body

DNA carries the blueprint for producing the proteins that build and regulate cells, tissues, and organs in the body. Through gene expression, it instructs cells on what proteins to make and how to make them.

However, DNA can undergo modifications and lose its normal function when it interacts with both physical and chemical agents. For instance, DNA can interact with byproducts of normal physiological processes, such as reactive oxygen species, or with environmental agents like UV radiation,which can induce irreparable DNA damage.

The resulting alterations and damage to the DNA by these factors can interfere with its role in the preservation and transmission of genetic materials. When DNA damage disrupts genes that regulate cellular division, it can initiate cancer development.It is also implicated in a myriad of neurodegenerative diseases, where it may cause cell death. The accumulation of unrepaired DNA damage is recognized as a key driver in the aging process, including both naturally occurring and premature aging.

Types of DNA Damage

DNA possesses robust mechanisms for repairing damage when it occurs. However, genes involved in these repair pathways, along with DNA polymerase (the enzyme responsible for both replication and repair), can sometimes introduce errors. When such mistakes accumulate, they can overload the cells with mutated DNA.

A 2018 review on the Mechanisms of DNA damage, repair, and mutagenesis broadly categorizes DNA damage into two types: endogenous or exogenous. This classification is dependent on whether damage arises from normal physiological processes within the body or from environmental stressors.

Endogenous DNA Damage

Endogenous DNA damage processes, also known as spontaneous DNA damage, mostly arise naturally from cellular metabolism and chemical instability of DNA.

DNA can react with water (causing hydrolytic damage) or with reactive oxygen species (ROS) produced during metabolism. These natural interactions can alter DNA structure, increasing the risk of genetic disorders and sporadic cancers over time.

Endogenous DNA damage processes include:

• Spontaneous base deamination: Occurs when human cells lose amine groups from bases such as cytosine, adenine, guanine, and 5-methylcytosine. This chemical alteration can convert one base into another. If such mispairing escapes correction by the DNA damage checkpoints, the unrepaired lesion may give rise to mutations and genomic instability.

• Abasic sites: These sites, also known as AP sites, form when the N-glycosyl bonds, which link the sugar-phosphate moiety backbone to the bases, are broken by hydrolysis or DNA glycosylase. This chemical change may subsequently cause the formation of single-strand breaks. If left unrepaired, abasic sites can cause replication block mutations, or trigger programmed cell death. During repair, DNA ligase plays a key role in sealing the breaks and restoring the integrity of the DNA molecule.

• Oxidative DNA damage: Reactive Oxygen Species (ROS), typically generated as byproducts of the electron transport chain, can oxidize DNAbases and modify the deoxyribose sugar.Such oxidative DNA damage is associated with aging and chronic diseases including cancer, diabetes, Parkinson’s disease, Alzheimer’s disease, and heart failure. An efficient DNA checkpoint ensures the detection and activation of pathways that repair DNA lesions and prevent long-term harm to cellular functions

• DNA methylation: This is an epigenetic occurrence where methyl groups are added to cytosine bases. While not a classical lesion, abnormal DNA methylation patterns can mimic DNA damage by altering gene expression. Proper responses to DNA damage involve balancing DNA repair mechanisms with epigenetic regulation to maintain genome stability.

Together, these endogenous DNA damage processes highlight the constant vulnerability of the genome and the essential need for efficient DNA repair pathways to preserve genomic integrity and maintain healthy cellular function.

Exogenous DNA Damage 

Exogenous DNA damage occurs when environmental, physical, or chemical agents damage the DNA.

They include: 

• Ionizing radiation DNA damage: Ionizing radiation from rocks, soil, cosmic radiation,and medical devices produces DNA-reactive free radicals that cause single-strand breaks and double-strand breaks (DSBs). Severe exposure overwhelms the cell’s repair capacity.

• Ultraviolet (UV) damage: The link between UV and DNA damage has long been recognized, with sunlight acting as a major source of exposure. UV radiation disrupts DNA replication by creating covalent bonds between adjacent cytosine and thymine bases (pyrimidines), forming dimers. These distortions compromise genome integrity, but specialized DNA repair enzymes and DNA polymerases are often recruited to repair damaged DNA.

• Alkylating agents: Found in tobacco smoke, biomass burning, industrial processing, and certain chemotherapeutic agents, alkylating agents attach to DNA bases to form DNA adducts. This type of modification interferes with normal base pairing, increasing the risk of mutation. Effective DNA repair processes are therefore essential to eliminate these lesions before they progress into cancerous changes.

Other sources of exogenous DNA damage are aromatic amines, polycyclic aromatic hydrocarbons, toxins (aflatoxin from Aspergillus species), environmental stressors such as extreme heat or cold, hypoxia, and oxidative stress.

While our control over endogenous sources of DNA damage is very limited, we do have some control over environmental factors and other exogenous sources of DNA damage. We can achieve this by following protective lifestyle choices.

Common Causes of DNA Damage

Common causes of DNA damage may arise from endogenous or exogenous sources. These sources often interact with the DNA to either alter the sequence of the DNA arrangement or potentially cause mutations that could result in epigenetic changes that affect gene expression.

These sources include :

• Reactive oxygen species
• Ionizing radiation
• UV light
• Environmental factors
• Carcinogens
• Aldehydes
• Hydrolysis
• Reactive metabolites like advanced glycation endproducts (AGEs)

Whether the source is internal or external, the body’s ability to recognize and repair this damage determines how well our cells maintain genomic stability and overall health.

Environmental Factors Leading to DNA Damage

Environmental factors leading to DNA damage can be from natural sources or human activities.

These factors include:

• UV radiation: Sunlight is the primary source of UV light. While it’s critical for the production of vitamin D, it can become a DNA-damaging agent with excessive exposure and accompanying risk of skin cancer. UV and DNA damage occur when radiation from sunlight interferes with bonding between the nucleotides forming DNA lesions.

• Radon: A radioactive gas that is formed from the decay of uranium-commonly found in all rocks and soils. It is usually found in high concentration in caves, mines,water treatment facilities, and in areas with poor ventilation. Long exposure can cause lung cancer. Radon exposure can lead to DNA damage double-strand breaks primarily through alpha radiation emitted from its decaying products.

• Food mutagens: These can be formed from cooking at high temperatures. Suspected mutagens such as polycyclic aromatic hydrocarbons and heterocyclic amines are formed in the process. Mold-contaminated foods containing aflatoxin from Aspergillus species are also confirmed mutagens. Generally, these food mutagens cause damage by altering DNA bases forming DNA adducts, high exposure could lead to chromosomal instability.
• Cigarette smoke: Cigarette smoke contains acetaldehyde, formaldehyde, benzene, arsenic, vinyl chloride, and other carcinogenic chemicals. These chemicals, with long exposure cause DNA lesions by forming DNA adducts.

• Industrial chemicals: Asbestos, vinyl chloride, benzene, arsenic, cadmium and cadmium compounds, and acrylonitrile are all industrial chemicals that can cause DNA damage and cancer in humans by forming DNA adducts and causing oxidative stress.

Simple safety measures such as wearing protective gear at work, limiting sun exposure, avoiding mold-contaminated food, and cooking at moderate temperatures, can lower the risk of DNA damage and, in turn, reduce your overall risk of cancer.

Symptoms and Signs of DNA Damage

There are no direct clinical symptoms of DNA damage, however, the manifestations of certain diseases could be an indicator that your DNA has sustained some level of damage.

For example, patients with syndromes resulting from defective nucleotide excision repair (NER) or translesion synthesis (TLS)usually present with high levels of skin cancer in areas exposed to UV light.

Additionally, some defects in NER can also lead to xerodermapigmentosum and more severe symptoms, such as neurological and developmental impairment and signs of aging.

DNA Damage and Its Role in Aging

According to the 2023 article on the central role of DNA damage in the aging process, DNA repair defects cause damage that drives the accelerated aging seen in progeroid syndromes. While aging is a normal biological process, the inability to properly repair DNA damage caused by mutagens accelerates this process, leading to premature aging.

For instance, greying hair, increased risk of type 2 diabetes, osteoporosis, and cataracts are common manifestations of premature aging observed in Werner Syndrome. This condition has been traced to mutations in the WRN gene, which plays a crucial role in DNA replication, repair, transcription, and telomere maintenance.

Another manifestation of the effects of DNA damage and aging is seen in Cockayne syndrome, caused by defective transcription-coupled repair, growth failure, photosensitivity, and neurological decline that resemble premature aging.Overall, mutations that compromise DNA maintenance and repair significantly contribute to premature aging and related syndromes. While we have highlighted its effects in Werner and Cockayne syndrome, other conditions such as Bloom Syndrome, Xeroderma pigmentosum, and Fanconi anemia also stem from defects in DNA repair and maintenance.

Health Conditions Linked to DNA Damage

DNA repair defects and damage response mechanisms are associated with a wide range of human disorders.

Some examples include: 

• Werner Syndrome
• Bloom syndrome
• Rothmund-Thompson syndrome
• Cockayne syndrome
• Xeroderma pigmentosum
• Fanconi anemia
• Ataxia telangiectasia
• Hutchinson-Gilford progeria syndrome
• Nijmegen breakage syndrome

All of these disorders arise from instability due to mutations in the genes responsible for repairing DNA damage.

How DNA Repair Mechanisms Work

Each cell’s DNA sustains tens of thousands of lesions daily. To preserve genomic integrity, mammalian cells have evolved robust mechanisms to counteract this damage, such as base excision repair and recombination using homologous DNA sequences. When DNA is injured, lesion-specific sensor proteins trigger the DNA damage response pathways (DDR). This is a coordinated network that detects the lesion, initiates signaling cascades, and activates appropriate repair pathways.

The various repair pathways are regulated by DDR kinases, which regulate the activity of repair proteins, induce changes to chromatin structure near the damage site, and make the cellular environment conducive to repair.

The various major DNA repair pathways and how they fix DNA damage include:

• Base excision repair (BER): Removes damaged bases.
• Mismatch repair (MMR): Recognizes base incorporation errors and base damage.
• Nucleotide excision repair (NER): Removes bulky DNA adducts.
• Interstrand crosslink repair (ICL): Removes interstrand cross-links.
• DNA double-strand break (DSB) repair pathway: This pathway includes homologous repair (HR) and nonhomologous end joining (NHEJ). Both mechanisms act to repair breaks in the DNA backbone.

Some of these DNA damage repair machinery can work independently to repair damaged DNA, but in complicated cases involving multiple lesions, the DDR is activated to coordinate the repairs.

Preventive Strategies for Reducing DNA Damage

A good starting point for protecting your DNA is to identify agents known to cause damage, particularly established carcinogens.

Below are some steps you can take to reduce your chances of damaging your DNA:

• Eat fruits and vegetables that contain phytochemicals that may help reduce DNA damage
• Engage in moderate physical activity which reduces oxidative stress and supports DNA protection.
• Make sure to get sufficient deep sleep to produce adequate melatonin, which plays an important role in the protection of mitochondrial and nuclear DNA.
• Limit exposure to sunlight.
• Avoid smoking.
• Reduce exposure to chemical carcinogens.

While these measures are not foolproof, they reduce your risk significantly and support the body’s natural DNA repair pathways.

Future Research and Advances in DNA Repair

Next-generation sequencing (NGS) is a major tool in the future of DNA repair that provides an unprecedented window into aspects of the human genome that were previously inaccessible or poorly understood.

Here are five ways that NGS would help in aiding DNA repair in the future:

• It can help identify regions prone to DNA breaks, mutations, or rearrangements caused by defective repair.
• By sequencing cancer genomes or rare disease genomes, NGS can detect mutations in DNA repair genes, linking them to disease risk or therapy response.
• High-throughput sequencing of repair junctions allows scientists to see whether HR (precise) or NHEJ (error-prone) repair double-strand breaks.
• Because NGS also applies to RNA, it can quantify expression levels of DNA repair genes under stress, therapy, or aging.
• DNA methylation and chromatin accessibility, revealed by NGS-based methods, can show how repair processes are regulated at the epigenetic level.

Other areas that are being explored include the use of non-coding RNAs, sirtuins, circadian genes, and protein chaperones. All of them fine-tune DNA repair and could be extrapolated to inform future therapies.

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Frequently Asked Questions 

What destroys DNA in the body?

DNA in the body can be destroyed by factors like ultraviolet (UV) radiation, toxic chemicals, pollution, smoking, and reactive oxygen species produced during normal metabolism.

Is DNA damage permanent?

Not always. Most DNA damage is not permanent because the body has repair systems in place to resolve damage, but if it is too severe or the repair process fails, damage can become permanent and lead to mutations or disease.

Which foods help DNA repair?

Foods rich in antioxidants and specific micronutrients, such as vitamins C, E, B12, folate, zinc, and selenium, help support DNA repair. These nutrients can be found in a variety of fruits and vegetables like lemons, broccoli, and leafy greens, as well as nuts, seeds, legumes, and soy products. Eating whole foods with these beneficial compounds is generally more effective than relying on supplements alone.

What happens when DNA is mutated?

When DNA is mutated, it can cause various changes. Some changes may be beneficial, neutral, or even harmful. Mutations can alter the protein-coding sequence, potentially leading to a non-functional or altered protein. While these changes can result in diseases like cancer, chronic illnesses, or genetic disorders; they can also provide the genetic variation necessary for evolution.

What viruses cause DNA damage?

Several viruses can cause DNA damage by inserting their genetic material into host cells, triggering inflammation, or producing proteins that interfere with DNA repair. Some notable examples include: Human Papillomavirus (HPV), Hepatitis B Virus (HBV), Epstein–Barr Virus (EBV), Human Immunodeficiency Virus (HIV), and many others.

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Deoxyribonucleic acid (DNA)

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Exploring DNA Damage and Repair Mechanisms: A Review with Computational Insights

 DNA Damage and Repair in Degenerative Diseases 2016

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DNA methylation 

DNA adducts-chemical addons

DNA damage causes mutations

The central role of DNA damage in the aging process

Genetic and Environmental Influence on DNA Strand Break Repair: A Twin Study

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Radon

Radon Exposure and Cancer Risk: Assessing Genetic and Protein Markers in Affected Populations

Possible Genetic Risk from Heat-Damaged DNA in Food

Harmful Chemicals in Tobacco Products

Cancer

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