DNA damages

Definition: All cells can sustain DNA damage from various sources that are conveniently classified as either endogenous or exogenous in origin.

In human cells, both normal metabolic activities and environmental factors such as UV light 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 ability to transcribe the gene that the affected DNA encodes.

Other lesions induce potentially harmful mutations in the cell genome, which affect the survival of its daughter cells after it undergoes mitosis. Consequently, the DNA repair process is constantly active as it responds to damage in the DNA structure.

A cell that has accumulated a large amount of DNA damage, or one that no longer effectively repairs damage incurred to its DNA, can enter one of three possible states:

1. an irreversible state of dormancy, known as senescence
2. cell suicide, also known as apoptosis or programmed cell death
3. unregulated cell division, which can lead to the formation of a tumor that is cancerous

Types of DNA damage

There are four main types of damage to DNA due to endogenous cellular processes:

1. oxidation of bases [e.g. 8-oxo-7,8-dihydroguanine (8-oxoG)] and generation of DNA strand interruptions from reactive oxygen species.

2. alkylation of bases (usually methylation), such as formation of 7-methylguanine, 1-methyladenine, O6 methylguanine.

3. hydrolysis of bases, such as deamination, depurination and depyrimidination.

4. mismatch of bases, due to errors in DNA replication, in which the wrong DNA base is stitched into place in a newly forming DNA strand, or a DNA base is skipped over or mistakenly inserted.

Damage caused by exogenous agents comes in many forms. Some examples are:

1. UV light causes crosslinking between adjacent cytosine and thymine bases creating pyrimidine dimers.

2. Ionizing radiation such as that created by radioactive decay or in cosmic rays causes breaks in DNA strands.

3. Thermal disruption at elevated temperature increases the rate of depurination (loss of purine bases from the DNA backbone) and single strand breaks. For example, hydrolytic depurination is seen in the thermophilic bacteria, which grow in hot springs at 85–250 °C.[3] The rate of depurination (300 purine residues per genome per generation) is too high in these species to be repaired by normal repair machinery, hence a possibility of an adaptive response cannot be ruled out.

4. Industrial chemicals such as vinyl chloride and hydrogen peroxide, and environmental chemicals such as polycyclic hydrocarbons found in smoke, soot and tar create a huge diversity of DNA adducts- ethenobases, oxidized bases, alkylated phosphotriesters and crosslinking of DNA just to name a few.

Causes of DNA damage

endogenous DNA damage

incorporation of incorrect nucleotides during DNA replication
alterations in the chemistry of adenine, guanine or cytosine, each of which can spontaneously lose their exocyclic amino groups (deamination), generating xanthine, hypoxanthine or uracil, respectively, in DNA
incorporation of uracil, instead of thymine, from a deoxyuridine triphosphate (dUTP) pool, during DNA replication
spontaneous hydrolysis of the chemical (N-glycosylic) bond linking purines or pyrimidines to the deoxyribose backbone of DNA, resulting in depurination or depyrimidination
various chemical alterations in bases, principally pyrimidines, caused by reaction with reactive oxygen species (ROS) in cells.

environmental DNA damage (exogenous DNA damage)

ionizing radiation
ultraviolet radiation
naturally occurring and man-made chemicals that are reactive with DNA
- anti-cancer chemical agents

Base damage (as well as other types of DNA damage such as strand breaks DNA damage) is believed to result in a signal that leads to various cellular responses in eukaryotic cells. The precise nature of this signal is not well understood, but might involve arrested DNA replication and/or arrested RNA polymerase II transcription.

The signal is transduced through signalling cascades to the ultimate effector responses shown in the figure. These include:

(a) the activation of cell-cycle-checkpoint pathways that arrest cell-cycle progression, thereby providing increased time for various DNA repair or other cellular response mechanisms to operate;
(b) the coordinated upregulation of a large number of genes, the function of many of which, and their relationship to cellular survival, remains to be determined;
(c) pathways for programmed cell death (apoptosis), presumably activated when other cellular response pathways will not be sufficiently efficacious;
(d) multiple biochemical pathways for the bypass of base damage, often resulting in mutations;
(e) multiple distinct DNA repair pathways.

The total complement of cellular responses is geared to the particular type of damage sustained, such that not all the effector responses mentioned operate simultaneously.

DNA damage

Genotoxic chemicals, ionizing radiation and other physical agents (e.g., UV light) create a wide variety of different types of DNA lesions (e.g., single strand breaks, base damage, double strand breaks and DNA-protein cross links).

Cells possess a multitude of biochemical mechanisms that can correctly repair most, if not all, types of DNA lesions. However once a DNA lesions is formed, it is likely that this DNA lesion will have a non-zero probability that some physiochemical or biophysical process will convert this damage into a point mutation or chromosome aberration.

In other words, there is most likely at least a small chance that the initial DNA lesions created by a physical or chemical agent will be misrepaired or become irreversibly fixed (unrepairable).

DNA damage, due to normal metabolic processes inside the cell, occurs at a rate of 50,000 to 500,000 molecular lesions per cell per day. However, many more sources of damage can drive this rate even higher.

Whilst this constitutes only 0.0002% of the human genome’s 3,000,000,000 (3 billion) bases, a single unrepaired lesion to a critical cancer-related gene (such as a tumor suppressor gene) can have catastrophic consequences for an individual.

DNA damage can be subdivided into two main types:

endogenous damage such as attack by reactive oxygen species (ROS or oxygen radicals) produced from normal metabolic byproducts (spontaneous mutation)

exogenous damage caused by external agents

radiations
- X-rays and ionizing radiations
- cancer radiotherapy
- ultraviolet [UV-light 200-300nm] radiation from the sun
- other radiation frequencies, including x-rays and gamma rays

hydrolysis
thermal disruption
certain plant toxins
human-made mutagenic chemicals
- hydrocarbons from cigarette smoke
- food-borne carcinogens

cancer chemotherapy (Antitumor agents)
- alkylators

replication errors

Before cell division the replication of damaged DNA can lead to the incorporation of wrong bases opposite damaged ones.

After the wrong bases are inherited by daughter cells these become mutated cells (cells that carry mutations), and there is no way back (except through the rare processes of back mutation and gene conversion).

Types of damage

Endogenous damage affects the primary rather than secondary structure of the double helix. It can be subdivided into four classes:

oxidation of bases [e.g. 8-oxo-7,8-dihydroguanine (8-oxoG)] and generation of DNA strand interruptions from reactive oxygen species,
alkylation of bases (usually methylation), such as formation of 7-methylguanine
hydrolysis of bases, such as depurination and depyrimidination.
mismatch of bases, due to DNA replication in which the wrong DNA base is stitched into place in a newly forming DNA strand.

DNA damage tolerance

When cells that are actively replicating DNA encounter sites of base damage or strand breaks, replication might stall or arrest. In this situation, cells rely on DNA-damage-tolerance mechanisms to bypass the damage effectively.

Translesion DNA synthesis

One of these mechanisms, known as translesion DNA synthesis, is supported by specialized DNA polymerases that are able to catalyse nucleotide incorporation opposite lesions that cannot be negotiated by high-fidelity replicative polymerases.

Alternative replication strategies

A second category of tolerance mechanism involves alternative replication strategies that obviate the need to replicate directly across sites of template-strand damage.

Consequences

Cells cannot function if DNA damage corrupts the integrity and accessibility of essential information in the genome (but cells remain superficially functional when so-called "non-essential" genes are missing or damaged).

Depending on the type of damage inflicted on the DNA’s double helical structure, a variety of repair strategies have evolved to restore lost information.

If possible, cells use the unmodified complementary strand of the DNA or the sister chromatid as a template to losslessly recover the original information.

Without access to a template, cells use an error-prone recovery mechanism known as translesion synthesis as a last resort.

DNA damage detection

Damage to DNA alters the spatial configuration of the helix and such alterations can be detected by the cell. Once damage is localized, specific DNA repair molecules bind at or near the site of damage, inducing other molecules to bind and form a complex that enables the actual repair to take place.

The types of molecules involved and the mechanism of repair that is mobilized depend on the type of damage that has occurred and the phase of the cell cycle that the cell is in.

Nuclear DNA damage versus mitochondrial DNA damage

In human, and eukaryotic cells in general, DNA is found in two cellular locations: inside the nucleus (nuclear DNA or nDNA) and inside the mitochondria (mitochondrial DNA or mtDNA).

Nuclear DNA (nDNA) exists in large-scale aggregate structures known as chromosomes, which are composed of DNA wound up around bead-like proteins called histones. Whenever a cell needs to express the genetic information encoded in its nDNA the required chromosomal region is unravelled, genes located therein are expressed, and then the region is condensed back to its quiescent conformation.

Mitochondrial DNA (mtDNA) is located inside mitochondria organelles, exists in multiple copies, and is also tightly associated with a number of proteins to form a complex known as the nucleoid. Inside mitochondria, reactive oxygen species (ROS), or free radicals, byproducts of the constant production of adenosine triphosphate (ATP) via oxidative phosphorylation, create a highly oxidative environment that is known to damage mtDNA.

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