Molecular mechanism of mutations induced by

known chemical mutagens

PromilaPh.D. BiotechnologyGJU S&T Hisar

•Some of the important types of agents which is used in artificial induction of mutations are: (i) Chemical mutagens and (ii) (ii) Physical mutagens

•The spontaneous mutation rate is very low at all the loci in all the organisms.

•Muller’s experiments decided that the mutation rate is much higher in the progeny of Drosophila when treated with X-rays.

•Any physical or chemical agent which is used in artificial induction of mutations is called mutagen.

(i) Chemical mutagens:Chemical mutagens are used in the following ways:

(a) Incorporation of base analogues:

•The two commonly used base analogues are 5-Bromouracil (5BU) and 5 Fluorouracil (5FU).

•Both are analogous bases to thymine of DNA, but 5BU or 5FU pairs with guanine instead of thymine’s natural pair adenine, thus producing 5BU-G or 5FU-G pairing rather than T-A pairing.

• It disturbs replication, transcription and translation mechanisms of DNA molecule.

•Fig. Mechanism of mutation induced by 5-bromouracil. This molecule has two tautomeric isoforms. Its keto form (BUk) pairs with adenine whereas its enol form (BUe) pairs with guanine.

•Suppose in the first replication the keto form was incorporated into a new DNA strand. During the second replication, if the keto form undergoes a tautomeric shift to the enol form, it will cause A:T to G:C mutation.

(b) Methylating agent:

•Some of chemicals like RN (CH2 Cl)2 or nitrogen mustards cause addition of methyl group to the nitrogen bases of DNA.

• For example, cytosine on methylation forms 5-methyl cytosine which prevents the separation of DNA strands for replication and transcription.

(c) Acridine dyes:

•Certain organic dyes such as acridine orange and proflavine causes insertion or deletion of nitrogen bases in a gene.

• Acridines may get inserted in between nitrogen bases of DNA; as a result, frame shift of the genetic code takes place and thus changing the whole lot of genetic information (codon).

•These are also known as Gibberish or frame-shift mutations because such mutations form nonsense polypeptide chain or codon.

(d) Deamination of bases:•Some chemicals like nitrous oxide deaminate (removal of NH2 or amino group) the nitrogen basis and therefore, change the codon of DNA.

• Nitrous oxide deaminate adenine to form hypoxanthine which has guanine like properties.

•As a result of which A-T pairing in DNA molecule will be replaced by G-C pairing thus causing gene mutation.

• Nitrous oxide can also change cytosine to uracil and guanine to xanthine. As a result of deamination the replication, transcription and translation are disturbed.

Free radicals •Hydroxylamine and free radicals may modify base structures, resulting in mispairing.

Figure (a) Base structures induced by free radicals. (b) The base change induced by NH2OH.

(ii) Physical mutagens:(a) High energy radiations:•All types of energy that can change the chemical structure of genes or chromosomes, induce mutations.

•For example X-rays, alpha rays, gamma rays, beta rays, cosmic rays, known as ionizing radiations and proton and neutron produce an ionizing effect on DNA molecules.

•They distort or break DNA duplex and disturb the replication. Ultraviolet rays are non-ionizing radiations and produce thymine dimers.

(b) Temperature:

•A rise in temperature may lead to disturbance in the genes thus causing mutations. Rarely, low temperature treatment may also cause mutations as in paddy.

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