What are the Causes of DNA damage?

What is DNA Damage Response? When Watson and Crick described the double helix structure of DNA and proposed its semi-conservative replication based on specific base pairings to explain the faithful transmission of genetic information from generation to generation mechanism to explain spontaneous mutations.

 

Watson and Crick pointed out that the structures of the bases in DNA are not static. Hydrogen atoms can move from one position in a purine or pyrimidine to another position, for example, an amino group to a ring nitrogen. Such chemical functions are called ‘Tautomeric shifts’.

 

DNA Damage: The Causes of DNA damage

 

Although tautomeric shifts are rare, they may be of considerable importance in DNA metabolism since they alter the base pairing potential of the bases. In the common stable form, adenine always pairs with thymine guanine always pairs with cytosine. But, these forms infrequently undergo tautomeric forms infrequently undergo tautomeric shifts to less stable enol and imino forms.

Tautomeric forms of nitrogenous forms

Tautomeric forms of the four common bases in DNA. The shifts of hydrogen atoms between the number 3 and number 4 positions of the pyrimidines and between the number 1 and number 6 positions of the purines change the base pairing potential of the bases.

Why DNA Damage?

 

They exist in this less stable tautomeric forms only for very short periods of time. However, if a base existed in its rare form at the moment that it was being replicated or being incorporated into a nascent DNA chain, a mutation might result in adenine-cytosine and guanine-thymine base pairs.

DNA damage: AC and GT basepairs

Examples of mismatched AC and GT base pairs that can form when one of the purines or pyrimidines exists in a rare tautomeric form. Similar mismatched base pairs can form when thymine exists in its rare enol form or adenine exists in its rare imino form

 

The net effect of such an event and the subsequent replication required to segregate the ‘mismatched’ is an AT or GC or AT base pair substitution.

 

Mutations resulting from tautomeric shifts in the bases of DNA involve the replacement of purine and the replacement of pyrimidine in the complementary strand with the other pyrimidine. Such base pair substitutions care called ‘Transitions’.

 

Base pair substitutions involving the substitution of a purine for pyrimidine and vice versa are called transversions. These are possible eight different transversions.

Base substitutions of DNA

Base substitutions possible in DNA: Purine for Purine and Pyrimidine for Pyrimidine, Purine for Pyrimidine (dashed arrows) and vice versa (solid arrows)

 

The third type of point mutation involves the addition or deletion of one or a few base pairs. Base pair additions and deletions are collectively referred to as frameshift mutations because they alter the reading frame of all base pair triplets (specifying codons in mRNA and amino acids in the polypeptide gene product) in the gene detail to the mutation.

 

Frameshift mutations and the changes in the reading of genetic code

Frameshift mutation and the changes in the reading of genetic code

 

Suppose three residues or some multiple of three are added or subtracted the remaining residues will still be in the correct triplet sequence for coding the intended amino acids through mRNA transcription. Therefore, the result will be the formation of a peptide chain that has some amino acids missing or additional ones inserted.

 

If on the other hand, an error in replication changes one or two or some multiple not divisible by three, then the genetic code gets scrambled and wrong amino acid will be incorporated into the resultant polypeptide chain at nearly every position.

 

All the three above-described types of point mutations transitions, transversions, and frameshift mutations are present among spontaneously occurring mutations. A surprisingly large proportion of the spontaneous mutations studied in prokaryotes are found to be single base pair additions and deletions rather than base-pair substitutions.

What are Mutagens,

Types of DNA damage and its role

 

Mutagen: Mutagens are agents that cause mutations. What are the Causes of Mutation? What are Mutations and its types?

There are two classes of mutagens and types of DNA damage. The given below are a Types of Mutation:

Read this basic guide:

  • Radiation (Physical mutagens)
  • Chemical Mutagens

Radiation

 

All forms of high-energy radiation, ionizing (gamma and cosmic rays, neutrons) and non-ionizing (ultraviolet light) radiation that is capable of disrupting the chemical structure of chromosomes, have been found to be mutagenic. Natural radiation arising from cosmic rays and radioactive minerals (thorium, uranium, and radium) cause spontaneous mutations. Cosmic rays are the main source of spontaneous mutations. They occur in small amounts in our environment and are spontaneous mutations. They occur in small amounts in our environment and are known as background radiation. The intensity of cosmic rays increases with altitude.

 

The biological effect of different radiation is not equally harmful. It is dependent on the penetration and ionizing power if the rays.

 

Ionizing radiations like X-rays and gamma rays can penetrate deep into the matter. In doing so, they collide with atoms and cause the release of electrons bearing positively charged free radicals of ions. These ions, in turn, collide with other molecules, causing the release of further electrons. When an electron is dissipated, these free electrons attach to other atoms which then become negatively charged ions. These ions then undergo chemical reactions to neutralize their charge to reach a stable state. During these chemical reactions, the mutagenic effects of ionizing radiations are produced, causing chromosome breaks and irregularities in the DNA.

 

Non-ionizing radiation, like ultraviolet radiation, have longer wavelengths and carry much lower energy. They are hence, less penetrative, unlike X-rays. In human beings, they do not penetrate beyond the skin and hence the gonads remain unaffected by these UV rays, dissipate their energy to atoms they encounter and raise their electrons to a state of excitation. Molecules containing such excited electrons are chemically more reactive than in their normal stable status. Hence, like ionizing radiations, they also can cause mutations by alterations in the DNA molecule.

 

Man-made radiation

 

In 1927, H.J.Muller first demonstrated that mutation could be induced artificially by X-rays. He produced by X-rays treatment, a markedly increased frequency of sex-linked recessive lethal mutations in Drosophila melanogaster. This he was able to do by devising a technique facilitating the simple and accurate identification of a lethal mutation in the X-chromosomes of Drosophila.

 

This technique called the C/B (crossing-over lethal Bar eye) method or technique involves the rise of females, heterozygous for a normal X chromosome and an X-chromosome (the C/B chromosome) specifically constructed for his experiment.

 

He was awarded Nobel prize for this work in 1946 after the first two atom bombs were exploded over Hiroshima and Nagasaki in 1945 and the II World war ended abruptly and with it the atomic era and the great significance of his 1927 discovery had dawned.

 

The frequency of induced mutations is usually directly proportional to the dosage of irradiation.

 

Graph showing the proportion between the frequency of sex linked mutations

The graph showing the proportion between the frequency of sex-linked mutations and radiation dosage in Drosophila

 

The linear relationship between mutation rate and radiation dosage is important because it answers directly the frequently asked question of what is a safe level of irradiation. In fact, there is no such thing as a safe level because very low levels of irradiation over long periods of time (chronic irradiation) are as effective in inducing mutations as the same total dosage of irradiation administered at high intensity for short periods of time (acute irradiation).

 

This clearly has major practical significance in evaluating the effects of the increased exposure of living organisms to radiation that results from the testing and use of nuclear weapons, accidents in nuclear reactors (such as the Chernobyl reactor mishap in USSR, in 1986), sinking of nuclear submarines (such as the sinking of Russian nuclear submarine off the coast of Norway very recently) and so on, significantly alter the frequency of mutations. Low oxygen tension decreases mutations.

 

Environmental against that protect germ cells from radiation damage (DNA damage) decreases mutations. Environmental agents that protect germ cells from radiation damage often do so by lowering the oxygen concentration of tissues, while those that enhance the effectiveness of radiation, and oxygen.

 

Chromosomal aberrations resulting from ionizing radiation can be deletions, duplications, inversions or translocations.

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