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Acriflavin

Base pairs

Acriflavin

Base pairs children with missing limbs. Thalidomide interferes with the development of embryos as opposed to causing mutations. Although the mechanism responsible for the malformations remains uncertain, it is known that thalidomide prevents blood vessels from forming (i.e. it is anti-angiogenic), which may partly explain the drug's ability to cause birth defects.

High energy radiation damages DNA.

Ultraviolet radiation promotes formation of thymine dimers.

Radiation Causes Mutations

Some types of radiation cause mutations. High frequency electromagnetic radiation, ultraviolet radiation (UV light), X-rays and gamma rays (g-rays), directly damage DNA. X-rays and g-rays are ionizing radiation; that is, they react with water and other molecules to generate ions and free radicals, notably hydroxyl radicals. Ionizing radiation is responsible for about 70 percent of the radiation damage to DNA. The other 30 percent of the radiation damage is due to direct interaction of X-rays and g-rays with DNA itself. In the early days of molecular biology, X-rays were often used to generate mutations in the laboratory. X-rays tend to produce multiple mutations and often yield rearrangements of the DNA, such as deletions, inversions and translocations.

Ultraviolet radiation is electromagnetic radiation with wavelengths from 100 to 400 nm. It is nonionizing and acts directly on the DNA. The bases of DNA show an absorption peak at around 254 nm and UV close to this wavelength is absorbed very efficiently by DNA. In particular, UV causes two neighboring pyrimidine bases to cross-react with each other to give dimers. Thymine dimers are especially frequent (Fig. 13.16). Although DNA polymerase can proceed by skipping over thymine dimers, this leaves a single-stranded region that needs repairing. The repair process in turn causes the insertion of incorrect bases in the newly synthesized strand (see Ch. 14 for details on error-prone repair). This therefore results in mutation.

Ultraviolet radiation is emitted by the sun. Most of it is absorbed by the ozone layer in the upper atmosphere, so it does not reach the surface of the earth. Damage to the ozone layer by the chlorinated hydrocarbons used in aerosol sprays and refrigerants has allowed more UV radiation to reach the surface of this planet, especially in certain areas. This has probably contributed to the increased frequency of skin cancer noted in recent years.

In addition to electromagnetic radiation, there are other forms of radiation, such as the a-particles and b-particles emitted by radioactive materials along with ionizing radiation Radiation that ionizes molecules that it strikes

Spontaneous Mutations Can Be Caused by DNA Polymerase Errors 351

Spontaneous Mutations Can Be Caused by DNA Polymerase Errors 351

A) Ultraviolet light (UV) sometimes results in the formation of a thymine dimer (red). B) The detailed chemical structure of the thymine dimer is shown.

A) Ultraviolet light (UV) sometimes results in the formation of a thymine dimer (red). B) The detailed chemical structure of the thymine dimer is shown.

DNA polymerase makes spontaneous mistakes that result in mutations.

DNA polymerase may slip when replicating short sequence repeats.

y-rays. Most a-particles are too weak even to penetrate skin but P-particles may cause significant damage to DNA and other biological molecules. However, a-emitters can be mutagenic if they have entered the body, for example by being breathed in or swallowed.

Spontaneous Mutations Can Be Caused by DNA Polymerase Errors

The enzymes that replicate DNA during cell division are not perfect. They make errors at a rate that is low, but nonetheless significant over a long period of time. As discussed in Ch. 5, DNA polymerases carry out proofreading and check recently inserted nucleotides for mistakes before moving on. In some cases, the proofreading ability is part of the polymerase itself. In other cases, it is due to an accessory protein such as the DnaQ protein associated with E. coli DNA polymerase III. Cells carrying mutations that abolish or damage these proofreading abilities show much higher rates of spontaneous mutation. Genes that give rise to altered mutation rates when they themselves are mutated are known as mutator genes. Hence, E. coli dnaQ mutants were originally named mutD (for mutator D).

The error rate for DNA replication in Escherichia coli is approximately one base in 10 million. About 20 times as many errors occur in the lagging strand as in the leading strand. This probably results from DNA polymerase I having a less effective proofreading capability than DNA polymerase III. The lagging strand is made dis-continuously (see Ch. 5) and the gaps are filled in by DNA polymerase I, whereas the leading strand is all made by PolIII.

In addition to putting in an occasional wrong base, DNA polymerase may very rarely omit bases or insert extra bases. This is due to strand slippage. If a run of several identical bases occurs, the template strand and newly synthesized strand of DNA may mutator gene Gene whose mutation alters the mutation frequency of the organism, usually because it codes for a protein involved in DNA synthesis or repair proofreading Process that checks whether the correct nucleotide has been inserted into new DNA. Usually refers to DNA polymerase checking whether it has inserted the correct base

Template strand of DNA

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