A lesion in DNA is damage to the DNA molecule often caused by the denaturing in weak hydrogen bonds involved in base pairing; lesions may include the presence of an abnormal base in the DNA or damage to the sugar-phosphate backbone. Lesions can occur in the template strand or in the new strand being replicated. A lesion is a change in DNA that is visible like a kink in DNA due to abnormalities. A mutation, on the other hand, is a change in the sequence of chemically normal DNA. It is not an RNA or protein with a wrong sequence; it is only a change in DNA sequence. Unlike many mutations, lesions can be repaired. There are two ways mutations are commonly characterized. There are mutations that occur in germ-line cells and produce gametes, resulting in the mutation being passed on to the offspring. There are also mutations that occur in somatic cells which do not produce gametes and do not pass the mutation to the offspring. The second common way of characterization is spontaneous mutations and induced mutations. Spontaneous mutations are caused by natural mistakes in the chemical properties of DNA, while induced mutations are caused by environmental influences such as radiation. Anything that induces mutations is referred to as a mutagen. Mutagens occur on the replicated strand of newly formed DNA which has a different sequence due to the induced mutation. Mutagens may be internal to the cell, or external in the form of radiation or chemicals (Pages and Fuchs, 2002
If you can look at the molecule and tell that there is a chemical problem with the DNA, then it is a lesion.
Spontaneous Lesion Mechanisms
A spontaneous mutation is one that occurs within cellular processes. A lesion is chemically abnormal DNA, such as bases pairing that are not meant to pair, and usually ends up causing a mutation, a change in the sequence of chemically normal DNA, when the molecule with a lesion is replicated. The two main ways by which a lesion can occur are transition and transversion. A transition is the substitution of a purine for a purine and a pyrimidine for a pyrimidine. They are much more common than transversions, even though there are more ways for transversion to occur. A transversion is the substitution of a purine for a pyrimidine and vice versa. When transversions occur there is a dramatic change in the chemical structure. For example, if a C paired with a T, the bond lengths would be larger and the bases would have to shift, or "slip" in order to pair with each other. Transversions can be caused by ionizing radiation and alkylating agents.
Deamination occurs in amino acids by the actions of oxidation, reduction, or hydrolysis (Frankel et al, 1980
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Deamination is the process of removing an amine group with the help of the enzyme, deaminase. An example of the deamination process in DNA is turning cytosine into uracil by a hydrolysis reaction. Deamination of cytosine is a significant source of spontaneous mutations(Bruce,1980). For example, if a cytosine in a normal GC pair turns into a uracil, then after replication, the uracil will bind to an adenine. At this point, this is a lesion because the presence of uracil causes the DNA to be chemically abnormal. After the next replication, however, the adenine will bind to a thymine. This is a transition mutation.
Deamination by Ana Gonzalez
Tautomeric shifts, or tautomeric transitions, are one of the causes of spontaneous mutations of DNA in nature (Golo and Volkov 2003
). The four nucleotides that make up DNA give DNA its capacity to store genetic information. Most DNA contains regular pairs of nucleic acid bases; when in their normal states, the bases adenine and thymine regularly pair together to form an AT pair and similarly, cytosine and guanine regularly pair together to form a CG pair. However, these four nucleic acid bases also exist, though rarely, in tautomeric forms apart from their normal state that have slightly higher energies (Tsolakidis and Kaxiras 2005
). Thymine and guanine are normally in their keto-tautomeric form, but when the hydrogen from their NH group shifts to the double bonded oxygen, forming an OH group, the base is in its rare enol form (Tsolakidis and Kaxiras 2005
). Similarly, adenine and cytosine are regularly in their amino form, but when a hydrogen from their NH2 group shifts to the single nitrogen atom in the ring to form an NH group, the base is in its rare imino form (Tsolakidis and Kaxiras 2005
). These tautomeric forms are depicted in figure 1 below. These tautomers can still form hydrogen bonds for base pairing, but due to the hydrogen relocations, they bond to normal bases of the right type (pyrimidine or purine), but the wrong base, resulting in incorrect base pairs. Each tautomer pairs with the wrong base of the right type. The rare enol form of T (denoted by T*) pairs with the normal keto form of guanine, forming a T*G pair (Tsolakidis and Kaxiras 2005
). Similarly, enol guanine pairs with keto thymine (G*T), imino cytosine with amino adenine (C*A), and imino adenine with amino cytosine (A*C) (Tsolakidis and Kaxiras 2005
). Therefore, when DNA undergoes replication, a tautomeric form of a base leads to incorrect base pairing that yields an incorrect DNA sequence on the newly synthesized strand, forming what is called a lesion. During a second round of replication, transcription of this new strand with the wrong base pair leads to a mutation in the newly synthesized DNA transcribed on that strand.This alteration in the genetic information is called a transition mutation, or a mutation in which a purine is replaced by a purine, and a pyrimidine is replaced by a pyrimidine (Golo and Volkov 2003
It is important to note that in the following image the cytosine and thymine have been mislabeled. The cytosine tautomers are in row two displaying amino and imino forms while thymine has the keto and enol forms displayed in the last row.
Streisinger slipped mispairing
Streisinger slipped mispairing is a lesion found in the DNA strand which is thought to be responsible for many repetitive sequences in DNA (Streisinger and Owen 1985
). For example, the occurrence of polypyrimidine chunks in the DNA seem to happen too often to be caused by simple random molecular motion (Levinson and Gutman 1987
). Streisinger also made a model called The Streisinger Model. This model shows framshifts happen when the loops in the single strands are stabilized by the slipped mispairing of the DNA base pairs (thomas et al. 1998
). When the base pairs misalign a lesion is formed. These lesions occur when the new strand aligns incorrectly with the template strand during DNA synthesis (Lovett 2004
), which usually occurs when there are several identical bases next to each other in a strand. When the slippage occurs in the template strand it results in deletion of a nucleotide (Streisinger and Owen 1985
). When the slippage occurs in the newly synthesized strand a bulge is produced that will result in the addition of a nucleotide or multiple nucleotides (Streisinger and Owen 1985
). Both template strand slippage new strand slippage are shown in the simplified version of the Streisinger Model shown below. Repetitive sequences can cause bases to slip and pair with another base and cause a bulge with extra bases. Strand slippage is less likely to occur when the sequences do not repeat. There may be up to three consecutive unpaired bases creating a loop in the strand (Lovett 2004
). The lesion is considered a bulge effect, because the extra nucleotide or nucleotides in either strand sticks out from the rest of the strand for lack of a complementary base in the other strand (Streisinger and Owen 1985
). Different trials have been done to observe whether deletions or insertions seem to be most likely to occur, but so far no definite results have shown to favor either one (Levinson and Gutman 1987
). Studies have shown that once a sequence of repeat units occurs the likelihood of more slippage increases (Levinson and Gutman 1987
). This occurrence has been attributed to the fact that transitional mutations, in which a pyrimidine is replaced with another pyrimidine and a purine with another purine, are more likely to occur than transversional mutations, in which a purine replaces a pyrimidine or vice versa (Lovett 2004
). This occurrence often takes place in junk DNA rather than in genes, in which it could interrupt the coding of proteins.
Streisinger Slipped Mispairing (K. Patterson)
Induced mutations are those that occur due to an environmental agent or mutagen. Types of mutagens include chemicals, radiation, and viruses. The first induced mutations were created by treating Drosophila with X-rays. Using this approach, Mueller induced lethal mutations. Base analogs are considered to be chemically induced mutagens by substituting themselves for a normal nucleobase in nucleic acid.
Here's a youtube video that can help visualize what is going on as UV rays hit a DNA molecule.
Chemical mutagens work mostly by inducing point mutations. Point mutations occur when a single base pair of a gene is changed. These changes are classified as transitions or transversions.
The main types of chemical mutagens are base analogs, which substitute for a normal base, base modifiers, which chemically alter bases that are already in the DNA, and intercalating agents, which stack non-covalently between bases and cause insertions or deletions. Other types of chemical mutagens include but not limited to x-rays, gamma rays, intercalating agents, and ultraviolet light.
Base analogs are a type of chemical mutagens that have chemical structures similar to that of normal DNA bases. Their essential property is that they base-pair with two different bases thus making mutations because of their lack of consistency in base-pairing. Base analogs are incorporated into a DNA molecule during DNA replication since DNA polymerase isn’t able to distinguish between normal DNA bases and base analogs (Pierce 2007).
An example of is azydothymidine (AZT), it is a abse analog of thymine and gets taken into the DNA that was made during reverse transcription. The latter can cause several diseases like, mink encephalopathy and mad cow disease.
5-bromouracil is a base analog that substitutes for thymine. 5-bromo-deoxyuridine (5BU) can exist in two tautomeric forms: typically it exists in a keto form (T mimic) that pairs with A, but it can also exist in an enol form (C mimic) that pairs with G. When 5-bromouracil is in DNA it changes the interaction between DNA and proteins (Ogino, Fujii, Satou, Suzuki, Michishita, & Ayusawa 2002
). It is capable of inducing mutations. By substituting thymine with 5-bromourcail, it alters the chromatin structure by changing the interactions between DNA and the nuclear matrix (Ogino 2002
When inducing mutations with 5-BU, the base pairing of A:T will change to G:C (Ronen, Rahat, & Halevy 1976
). This is done by forcing a replicating phage DNA to incorporate 5-BU instead of thymine. The first step is to incorporate a guanine, instead of adenine, opposite 5-BU. Once this is done, the lesion will replicate to form the transition mutation of G:C (Ronen 1976
When studying the replication of DNA, 5-bromouracil can be used as a density label. It is commonly used in the synchro-transfer method (Huang, Ederle, Boice, & Romig 1968)
Certain oligonucleotids, called photo-cross-linkable aptamers, can be activated with ultraviolet light to form covalent linkages with another molecule (Jayasena 1999
). Modified libraries that have 5-bromouracil in them are used to generate these photo-cross-linkable aptamers (Jayasena 1999
5-BU substituting for thymine
Hydroxylamine is a chemical mutagen that causes transition mutations in DNA. Transition mutations are characterized by switching a purine with a purine; or a pyrimidine with a pyrimidine in the DNA backbone. Hydroxylamine tends to react with pyrimidines much more than purines. The nucleotide most often reactive with hydroxylamine is cytosine. Reactions have also been seen with other compounds such as 5-hydroxymethyl cytosine (HMC), 5-methylcytosine, thymine, and 5-bromouracil. The primary reaction of hydroxylamine is at the 4' carbon of cytosine. In this reaction the hydroxylamine causes the pyrimidine ring to open up therefore disrupting its resonance form. It is proposed that the bond between the 3-N and 4-C positions on the pyrimidine ring breaks, then once placed in an acidic environment the ring closes. This yields a carbon at the 4 position that is double bonded to nitrogen, which is bound to a hydroxyl group. Through experimentation, Freese et al. determined that acidity was a major factor in the stability of products and interconversion among different pyrimidines takes place. Base pair transitions are induced because when cytosine is treated with hydroxylamine the 3 position hydrogen is sterically hindered by the coinciding hydrogen atom of guanine. Therefore, the hydroxylamine treated cytosine can at least make a single bond to adenine, which would replace the normally bound guanine during replication (Freese et al. 1961
Further studies have suggested that hydroxylamine not only causes a change in the pyrimidines chemically, it also alters them structurally. Taylor et al. found that DNA transcription was inhibited by hydroxylamine because of its ability to cause many single stranded cuts in the DNA backbone. These many slices compete for enzymes needed for repair. While RNA initiator sites are left without such enzymes further inhibiting transcription (Taylor A, Crist S, Jones O. 1970).
Nitrous acid (HNO2) is a chemical mutagen that can act upon DNA by deaminating cytosine to uracil and adenine to hypoxanthine (HX) (Frankel et al, 1980
). It is the only known mutagen which can induce deamination of adenine to hypoxanthine (Sidorkina et al, 1997
). HX can cause A-T to G-C transitions (Sidorkina et al, 1997
). It can also cause lesions in other ways. It can convert exocylic amino groups of DNA heterocycles to carbonyl groups, and in addition, can induce interstrand cross-links in duplex DNA, such as linking two guanines on opposite strands via a single shared exocyclic imino group (Edfeldt et al, 2004
The chemical structure of nitrous acid
Deamination of Cytosine to Uracil
Ethylmethane sulfonate (C3
) is an alkylating agent that causes induced mutations (Keightley et al. 2000)
. This agent alkylates the keto groups in the number-6 postiton of guanine and the number-4 position of thymine forming O-6-ethylguanine and O-4-ethylthymine, respectively.
When DNA replication occurs, DNA polymerase will pair thymine with O-6-ethylguanine as opposed to placing a cytosine with a normal guanine. After DNA replicates again, the once CG pair will become an AT pair thus causing a mutation. This type of mutation is known as a transition mutation, which is when a purine is replaced by another purine, or a pyrimidine is replaced by another pyrimidine (Keightley et al. 2000)
Although ethylmethane sulfonate can cause TA to CG transitions, it has been found to have mutagenic specificity, or “preference,” for GC to AT transitions. In a study done by Vidal et al. (1995)
, 239 ethylmethane-sulfonate-induced mutations of the N-terminal region of the lacI gene were observed. The authors found that all mutations were GC to AT transitions, which is consistent with EMS having a "preference" for alkylating guanine to O-6-ethylguanine (Videl et al. 1995)
. This type of mutation could possibly lead to cancer.
Ethylmethane Sulfonate (H. Moit)
Alkylation of the O-6 position of guanine by EMS (S. Payne)
Intercalating ligands are characterized by the possession of an extended electron defiant planar aromatic ring system ( Richards and Rodger, 2007). These chemicals insert themselves between the paired bases and the molecule becomes strained. The double helix gets so tight that the backbones stretch a little and the helixes become distorted (Montelone, 1998). Intercalation also leads to several other hydrodynamic changes in the DNA, but these effects are fully reversible upon removal of the intercalator as long as the DNA duplex structure is not destroyed by the process of removal (Richards and Rodger, 2007).
The distortion formed causes DNA polymerase to insert an extra base opposite the intercalating agent –insertion. Or, it may also be unable to add a complementary base, which will end up in deletion because there will be genetic material missing. Therefore, the distortion could lead to a mutation, either insertion or deletion. Example of intercalating agents are acridine orange, proflavin, ethidium bromide (Montelone, 1998).
Intercalating agents orient, or add, between DNA base pairs. Each agent varies on how much it will unwind and lengthen the DNA strand, depending on the molecule's shape and structure(Long and Barton, 1990). This affects DNA replication and transcription; usually stopping it. The illustration here, from Wiki Commons, shows three intercalating agents that have squeezed between base pairs of the DNA strands.
Intercalating agents are not always bad. Some, like acridine orange and ethidium bromide,are used in labs as dyes (Ulitzur and Weiser, 1981). Others are often used for cancer and tumor treatment because it stops DNA replication. This is important when treating cancer cells because you do not want those cells to replicate. A couple common chemical intercalating agents are Doxorubicin and Daunorubicin (Ophardt, 2003).
Mutation is a permanent change in the DNA sequence. Mutations that are passed from parents to child are called germline mutations. This type of mutation is present throughout a person’s life and it also can explain genetic disorders in which an affected child has a mutation in every cell, but has no family history of the disorder. There is another kind of mutation called somatic mutation which occurs in the DNA of a individual cell at some time during a person’s life. These changes can be caused by environmental factors such as ultraviolet radiation, or can occur if a mistake is made when DNA replication. Somatic cells cannot be passed on to the next generation.
Radiation causes a wide range of lesions in DNA. Ultraviolet, X-ray, and Gamma rays are high energy radiation. Larson and et al studied oxidative DNA damage in mice. Larson and et al introduced mice to 3.5Gy of radiation. Gamma rays can pass through cells to cause breakage in DNA. Ionization of molecules in cells can lead to cells reacting with other cells (Larson, et al). GC to TA transversions occurred causing mutations in tumor suppressor-genes (Larson, et al). Oxidative damage is related to tumors that contribute to cancer (Larson, et al.)
Overexposure to ultraviolet light has a detrimental effect on living organisms, because UV components of sunlight have been linked to a major risk for squamous cell carcinoma of the skin (Brash et al 1991
). This is a long term for “skin cancer”. It was found that 58% of squamous cell carcinomas of the skin involved a mutation of the p53 tumor suppressor gene (Brash et al 1991
). Electrons in a double bond can absorb exactly a UV proton. The mutations of DNA caused by UV light are noted by a distinctive C -> T transition at dipyrimidine sites (Brash et al 1991
). UVB rays are especially destructive to organisms because they directly damage their DNA by forming pyrimidine dimers. The radiation excites the DNA molecules, which creates abnormal covalent bonds to form between two adjacent pyrimidine bases, forming a pyrimidine dimer. During replication, DNA polymerase misreads the dimer as two adenine bases and adds two thymine bases instead. It was found that the wavelengths contributing the most to p53 gene mutations were found in the UVB region (Brash et al 1991
UV light Thymine Dimer Lesion
UVA radiation causes mutations because it forms 8oxoguanine which causes a transversion in DNA (Kozmin 2005). During DNA replication, the 8oxoguanine binds with adenine instead of cytosine. During the next DNA replication the adenine gets paired with thymine which causes the mutation.
In order to repair DNA damage from UVB rays, most organisms rely on nucleotide excision repair in order to remove the pyrimidine dimer lesions caused by the radiation. Plants are able to repair pyrimidine dimers more efficiently with the enzyme photolyase. Photolyase binds and removes the cyclobutane bridge that binds the dimers together. Even though NER is really accurate, when it comes to UV damaged DNA cells, direct reversal takes less time to get to the lesion to fix it than NER and therefore increases the chance that the UV damaged cell lives.
Along with nucleotide excision repair and direct reversal repair mechanisms being capable of repairing UV damaged DNA cells, recombinational DNA repair is responsible for about 50% of the survival of E. coli
cells after UV exposure (Spek et al, 2001)
Here is a youtuve video that explains how skin cancer can be induced by UV radiation. http://www.youtube.com/watch?v=o_7V-q5Rpho&feature=related
Pyrimidine dimers are lesions that are formed from cytosine or thymine bases in the DNA by photochemical reactions. UV light is absorbed in the 5-6 double bond of the pyrimidine, destabilizing it and forming a cyclobutane ring between the two successive pyrimidines. As a result nothing can pair with the dimer because of the altered structure, so polymerase III is inhibited and the replication fork movement is interrupted.
Successive Pyrimidine UV
- - -
----> Dimerized Pyrimidine
When the replication fork movement is interrupted, as it is when it comes across pyrimidine dimers, the SOS response is induced. During the SOS response, RecA protease is activated. RecA removes the LexA repressor on the SOS operon which then allows transcription of the genes 'umu
'C and D. These genes will be translated into DNA polymerase V. RecA also binds to the single-stranded DNA located after the replication fork creating a nucleofilament. Finally, RecA and ATP activate polV which will then bind at the stalled replication fork (Qingfei et al. 2009
). The stalled DNA polymerase III falls off the DNA strand. Pol V replaces it and begins replicating again (Schlacher et al. 2006
However, this is an error prone polymerase and it will add random bases to the strand opposite the lesion, base-pairing incorrectly and even matching a purine with a purine or a pyrimidine with a pyrimidine. It will often continue replicating further down the DNA strand after the lesion, until the return of DNA polymerase III. Translesion DNA synthesis, as this is called, creates a lot more lesions and mutations in the DNA where polV was replicating (Friedburg 2005
X-rays are a type of short wavelength electromagnetic ray radiation. The structure of a living cell, directly and indirectly, can be altered by the low-energy photons in x-rays. This is done by disturbing an atom’s composition by creating both a free electron and an ionized compound or by producing free radicals. Effects caused by this type of radiation are loss of tissue function and/or modifications in a cell component, mainly DNA (Bentur, 2008
). There have been findings that exposure to x-ray radiation causes phosphorylation of a histone protein, H2AX, in places of DNA double-strand breaks (BanAth et al, 2003
). In the past it was believed that it must be direct interaction of x-ray radiation and DNA to caused genetic mutations. Recently studies have been conducted that supports that even a low x-ray exposure affects cells that are not in direct contact with the radiation. Exposure gives rise to lack of genomic structure or stability in irradiated cells (cells that have been exposed to radiation) that can be passed on to their offspring over multiple generations of cell replications. Exposure also stimulates the discharge of cytokines and growth factors making communication between cells more difficult and not as clear. This causes the number of cells to increase that are involved in the response during communication (Basso, 2008
Free Radical Formation
X-rays can cause free radicals to form when they pass through skin by severing the bonds between two atoms. These free radicals have one unpaired electron and are very reactive. Some of the radicals that are formed from the x-rays can pass through cells and react with other compounds found in the organism. When the radicals react with other compounds, they produce another radical that can lead to a chain reaction. These radicals can also be moved throughout the organism (Gordy 1958
). If one of the radicals were to react with a base pair, then a lesion could form. After several replications of that gene containing the lesion, a mutation can result. Since these radicals can penetrate the skin and pass through tissues, the mutations that result can be either germ-line or somatic mutations.
In case you are wondering if the X-Rays done at a medical facility can be harmful, check out this video to find out. http://www.youtube.com/watch?v=Na4iRgRiWG4
Mutations can also be caused by viral infections.Germ-line Mutations
If a mutation occurs in a germ-line cell, then the mutation can be passed on to offspring (Bland,2003).Somatic Mutations
If a mutation occurs in a somatic cell, then the mutation would not be passed on to the offspring because somatic cells do not give rise to gametes (Bland, 2003). Somatic mutations are mutations that can occur in any cell in the body except the germ cell. These types of mutations are not something that can be passed from a parent to a child (nlm.gov). The reason they cannot be passed along from parent to child is because they do not occur in cells that give rise to gametes (McClean,1999). A somatic mutation can have many different affects on the body. It can have a small affect which doesn't cause much harm, or it can affect the health and overall development of a body. Somatic mutations occur in regular body cells. Somatic cells can be used in all non-germ-line tissues. If a mutation is present in one of the progenitor cells all of its daughter cells will also carry the mutation as well(McClean,1999).
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