DNA Damage/DNA Repair


DNA Damage


DNA damage is an abnormal chemical structure in DNA that can cause changes in the structure of the genetic material and prevent the replication mechanism from functioning and performing properly.



Various damaged chromosomes due to DNA damage


DNA Repair


DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage, resulting in as many as 1 million individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentiallypotentially harmful mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur, including double-strand breaks and DNA crosslinkages (interstrand crosslinks or ICLs). This can eventually lead to malignant tumors, or cancer as per the two hits.


The speed of DNA repair is related to many factors, such as cell type, cellular aging, and the external environment. However, as the cell accumulates large amounts of DNA damage and ages, the rate of DNA repair slows until it cannot keep up with the rate of ongoing DNA damage. At this point, the cell can suffer one of three fates:


1. Irreversible dormancy, known as senescence

2. Cell suicide, i.e. apoptosis or programmed cell death

3. Uncontrolled cell division, which can lead to the formation of tumors or cancers


Most cells in the human body first age, undergo irreversible DNA damage, and then enter apoptosis. In this case, apoptosis acts as a "last resort" to prevent cells from becoming cancerous and damaging the body.


During aging, changes in biosynthesis and material turnover reduces the efficiency of cell life activities, which inevitably leads to disease. The ability of a cell to repair DNA is extremely important to the integrity of its genome and to the normal function of the cell and even the organism. Many genes were previously shown life expectancy be involved in DNA damage repair and protection.


Molecular damage in the cells that form zygotes, if not repaired and corrected, will produce mutated progeny, thereby affecting the rate of evolution.


Nuclear DNA and Mitochondrial DNA Damage


DNA in human cells and most eukaryotic cells is located in two places within the cell: the nucleus and the mitochondriaNuclear DNA (nDNA for short) is assembled in large quantities in chromosomes; chromosomes are made up of DNA and bead-like proteins called histones wrapped around it. As long as a cell wants to express the genetic information encoded by its nDNA, its corresponding chromosomal region will be disassembled, and the gene located there will be expressed, and then the region will shrink back to its original static structure. Mitochondrial DNA (mtDNA for short) is localized within the organelle mitochondria and exists in several copies. mtDNA also binds tightly to many proteins to form complexes called nucleoids. Inside the mitochondria, reactive oxygen species (ROS) or free radicals, by-products of the oxidative phosphorylation reaction that generate adenosine triphosphate (ATP), result in a highly oxidative environment known to be detrimental to mtDNA.


Causes of DNA Damage


DNA damage can be divided into two major types:


1. Endogenous damage, such as damage caused by an attack by reactive oxygen species (free radicals), a by-product of normal metabolism (spontaneous mutation);

2. Exogenous damage, caused by external factors, such as:

(1) Ultraviolet rays from the sun [UV 200-300nm]

(2) Radiation of other frequencies, including X-rays and gamma rays

(3) Hydrolysis and Pyrolysis

(4) Certain phytotoxins

(5) Man-made mutant substances, such as certain hydrocarbons from smoking

(6) Tumor chemotherapy and radiation therapy


Before cell division, the replication of damaged DNA causes the wrong base to bind opposite the damaged base. After the daughter cells inherit the wrong base by genetic inheritance, they become mutant cells (cells with mutations), and there is no way back (except through rare reverse mutations and gene conversions).


Types of DNA  

The type of endogenous DNA damage mainly affects the primary structure of DNA (such as nucleotide-level structure, pairing, etc.), and only severe exogenous DNA damage has the opportunity to cause effects on DNA secondary structure (e.g., changes in the three-dimensional structure of the DNA level). There are five main forms of damage to the primary structure of DNA:


Nucleotide base oxidation: for example: [8-oxo-7,8-dihydroguanine (8-oxoG)], [Thymine glycol], etc. These are mainly intracellular reactive oxygen species (ROS) on DNA caused by the attack. In addition, ionizing radiation in the environment often causes the oxidation of bases.


Nucleotide base alkylation: or often called methylation, such as [O6-methylguanine], [N7-methylguanine], [N3-methyladenine] and so on.

Nucleotide base deamination: for example, uracil is formed by deamination of methylated cytosines

Nucleotide base hydrolysis: such as depurination or depyrimidination.

Nucleotide base mismatch: this is often caused by the insertion of the wrong nucleotide into a single strand of newly synthesized DNA during DNA replication.


And exogenous DNA damage, with the difference in exposure time and dose of exogenous factors, the form of DNA damage caused by it is also very different. The current study found that cells exposed to UV light cause DNA to form pyrimidine dimers, a well-defined type of exogenous DNA damage.


DNA Repair Mechanism


Since both endogenous and exogenous sources of DNA damage cannot be avoided, cells must take appropriate measures in the face of these forms of DNA damage. For a cell, the negative approach is to temporarily tolerate the existence of damage, and when the cell's genetic body is damaged to a certain extent, the cell can no longer continue to function; while the positive approach is to develop a corresponding approach to all possible DNA damage, with corresponding repair remedies to ensure the correctness of the genetic information in the gene. According to the research and development of molecular biology in recent years, scientists have found that the corresponding DNA repair mechanism can be found from yeasts that survive in the form of single cells to our human cells. Highly conserved and more fully demonstrated the harm caused by DNA damage was inevitable in the early stages of biological evolution. In the DNA repair mechanism in existing cells, the degree of DNA damage breaks can be divided into two types, one is single-strand damage, and the other is DNA double-strand break. The former repair mechanism usually requires the help of another corresponding template, while the latter, in the absence of another sequence as a template, turns to seek support through homologous chromosomal sequences or sister chromatids. In higher organisms, sometimes the repair of DNA double-strand breaks may not require any sequence as a template, and the broken part is directly joined, but this method of DNA repair may imply error-prone.

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