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Chapter 12: DNA Damage and Repair

12.1 DNA Mutations

12.2 Types of DNA Damage

12.3 Cellular Stress and DNA Damage Response

12.4 Mismatch Repair

12.5 Base Excision Repair

12.6 Nucleotide Excision Repair

12.7 Repair of Double-Stranded DNA breaks

12.8 Error-Prone Bypass and Translesion Synthesis

12.9 Practice Problems

12.10 References

12.1 DNA Mutations

The integrity of the DNA structure for cell viability is underscored by the vast amounts of cellular machinery dedicated to ensure its accurate replication, repair, and storage. Even still, mutations within the DNA are a fairly common event.

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Mutations are random changes that occur within the sequence of bases in DNA. They can be large scale, altering the structure of the chromosomes, or small scale where they only alter a few or even a single base or nucleotide. Mutations can occur for many reasons. For example, DNA mutations can be caused by mistakes made by the DNA polymerase during replication. As noted in chapter 9, DNA polymerases are highly processive enzymes that contain proofreading and editing functions. With these safeguards, their error rates are typically very low and range from one in a million bases to one in a billion bases. Even with such high fidelity, this error rate will lead to between 3 and 3,000 errors within the human genome for each cell undergoing DNA replication. DNA mutations can also result through the replication of DNA that has been damaged by endogenous or exogenous agents. The next section will highlight common types of DNA damage and their effects. If a DNA polymerase encounters a damaged DNA base in the template DNA during replication it may place a random nucleotide base across from the lesion. For example, an adenine-containing nucleotide will often be added across a lesion, regardless of what the correct match should be. This can lead to the formation of transition or transversion mutations.

A transition mutation is a point mutation that changes a purine nucleotide to another purine (A ↔ G) or a pyrimidine nucleotide to another pyrimidine (C ↔ T). Whereas, a transversion refers to the substitution of a purine for a pyrimidine or vice versa. Sometimes lesions may cause bases to be skipped during replication or cause extra nucleotides to be inserted into the backbone. DNA polymerases can also slip during the replication of regions of the DNA that have repeated sequences or large stretches repeating a single base. Larger lesions or cross-links in the DNA during replication can lead to more catastrophic DNA damage including DNA strand breaks. Mutations may also occur during the processes of mitosis and meiosis when sister chromatids and/or homologous chromosomes are being separated from one another.


In nature, mutagenesis, or the process of generating DNA mutations, can lead to changes that are harmful, or beneficial, or have no effect. Harmful mutations can lead to cancer and various heritable diseases, but beneficial mutations are the driving force of evolution. In 1927, Hermann Muller first demonstrated the effects of mutations with observable changes in chromosomes. He induced mutagenesis by irradiating fruit flies with X-rays.

When a mutation is caused by an environmental factor or a chemical agent, that agent is called a mutagen. Typical mutagens include chemicals, like those inhaled while smoking, and radiation, such as X-rays, ultraviolet light, and nuclear radiation. Different mutagens have a different modes of damaging DNA and are discussed further in the next section. It is important to note that DNA damage, in and of itself, does not necessarily lead to the formation of a mutation in the DNA. There are elaborate DNA repair processes designed to recognize and repair different types of DNA lesions. Fewer than 1 in 1,000 DNA lesions will actually result in a DNA mutation. The processes of DNA damage recognition and repair are the focus of later sections within this chapter.


Types of Mutations

There are a variety of types of mutations. Two major categories of mutations are germline mutations and somatic mutations.

Germline mutations occur in gametes, the sex cells, such as eggs and sperm. These mutations are especially significant because they can be transmitted to offspring and every cell in the offspring will have the mutations.Somatic mutations occur in other cells of the body. These mutations may have little effect on the organism because they are confined to just one cell and its daughter cells. Somatic mutations also cannot be passed on to offspring.

Mutations also differ in the way that the genetic material is changed. Mutations may change an entire chromosome or just one or a few nucleotides.


Chromosomal alterations are mutations that change chromosome structure or number. They occur when a section of a chromosome breaks off and rejoins incorrectly or does not rejoin at all. Possible ways these mutations can occur are illustrated in the figure below. Chromosomal alterations are very serious. They often result in the death of the cell or organism in which they occur. If the organism survives, it may be affected in multiple ways. An example of a human chromosomal alteration is the mutation that causes Down Syndrome. It is a duplication mutation that leads to developmental delays and other abnormalities. It occurs when the individual inherits an extra copy of chromosome 21. It is also called trisomy (“three-chromosome”) 21. Thus, large-scale mutations in chromosomal structure include: (1) Amplifications (including gene duplications) where repetition of a chromosomal segment or presence of extra piece of a chromosome broken piece of a chromosome may become attached to a homologous or non-homologous chromosome so that some of the genes are present in more than two doses leading to multiple copies of all chromosomal regions, increasing the dosage of the genes located within them, (2) Deletions of large chromosomal regions, leading to loss of the genes within those regions, and (3) Chromosomal Rearrangements such as translocations (which interchange of genetic parts from nonhomologous chromosomes), insertions (which insert segments of one chromosome into another nonhomologous chromosome), and inversions (which invert or flip a section of a chromosome into the opposite orientation)(Figure 12.1).

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Figure 12.1 Chromosomal Alterations. Chromosomal alterations are major changes in the genetic material.Image modified from Dietzel65

There are also smaller mutations that can occur that only alter a single nucleotide or a small number of nucleotides within a localized region of the DNA. These are classified according to how the DNA molecule is altered. One type, a point mutation, affects a single base and most commonly occurs when one base is substituted or replaced by another. Mutations also result from the addition of one or more bases, known as an insertion, or the removal of one or more bases, known as a deletion.

Point mutations may have a wide range of effects on protein function (Table 12.1 and Figure 12.2). As a consequence of the degeneracy of the genetic code, a point mutation will commonly result in the same amino acid being incorporated into the resulting polypeptide despite the sequence change. This change juniorg8.comld have no effect on the protein’s structure, and is thus called a silent mutation. A missense mutation results in a different amino acid being incorporated into the resulting polypeptide. The effect of a missense mutation depends on how chemically different the new amino acid is from the wild-type amino acid. The location of the changed amino acid within the protein also is important. For example, if the changed amino acid is part of the enzyme’s active site or greatly affects the shape of the enzyme, then the effect of the missense mutation may be significant. Many missense mutations result in proteins that are still functional, at least to some degree. Sometimes the effects of missense mutations may be only apparent under certain environmental conditions; such missense mutations are called conditional mutations. Rarely, a missense mutation may be beneficial. Under the right environmental conditions, this type of mutation may give the organism that harbors it a selective advantage. Yet another type of point mutation, called a nonsense mutation, converts a codon encoding an amino acid (a sense codon) into a stop codon (a nonsense codon). Nonsense mutations result in the synthesis of proteins that are shorter than the wild type and typically not functional (Summarized in Figure 12.3).

Table 6.6.1" role="presentation">12.1: Types of Point Mutations

TypeDescriptionExampleEffect
Silentmutated codon codes for the same amino acidCAA (glutamine) → CAG (glutamine)none
Missensemutated codon codes for a different amino acidCAA (glutamine) → CCA (proline)variable
Nonsensea mutated codon is a premature stop codonCAA (glutamine) → UAA (stop) usuallyserious
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Figure 12.2 The Potential Effects of Point Mutations on Protein Coding Regions. The image shows various types of point mutations (silent, missense, and nonsense), which may lead to change in the protein structure.Figure from: Jonsta247

Smaller scale deletions and insertions also cause various effects. Because codons are triplets of nucleotides, insertions or deletions in groups of three nucleotides may lead to the insertion or deletion of one or more amino acids and may not cause significant effects on the resulting protein’s functionality. However, frameshift mutations, caused by insertions or deletions of a number of nucleotides that are not a multiple of three are extremely problematic because a shift in the reading frame results (Figure 12.3). Because ribosomes read the mRNA in triplet codons, frameshift mutations can change every amino acid after the point of the mutation. The new reading frame may also include a stop codon before the end of the coding sequence. Consequently, proteins made from genes containing frameshift mutations are nearly always nonfunctional.

Figure 12.3. Summary of Small Scale Mutations on Protein Coding Regions. DNA alterations that lead to changes in the protein sequence encoded by the DNA can include point mutations, DNA insertions, and DNA deletions.

Figure from: Parker, et al (2019) Microbiology from Openstax

The majority of mutations have neither negative nor positive effects on the organism in which they occur. These mutations are called neutral mutations. Examples include silent point mutations, which are neutral because they do not change the amino acids in the proteins they encode.




Harmful mutations can also occur. Imagine making a random change in a complicated machine such as a car engine. The chance that the random change juniorg8.comld improve the functioning of the car is very small. The change is far more likely to result in a car that does not run well or perhaps does not run at all. By the same token, any random change in a gene’s DNA is more likely to result in the production of a protein that does not function normally or may not function at all, than in a mutation that improves the function. Such mutations are likely to be harmful. Harmful mutations may cause genetic disorders or cancer.

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A genetic disorder is a disease, syndrome, or other abnormal condition caused by a mutation in one or more genes or by a chromosomal alteration. An example of a genetic disorder is cystic fibrosis. A mutation in a single gene causes the body to produce thick, sticky mucus that clogs the lungs and blocks ducts in digestive organs. Genetic disorders are usually caused by gene mutations that occur within germline cells and are heritable in nature.Illnesses caused by mutations that occur within an individual, but are not passed on to their offspring, are mutations that occur in somatic cells. Cancer is a disease caused by an accumulation of mutations within somatic cells. It results in cells that grow out of control and form abnormal masses of cells called tumors. It is generally caused by mutations in genes that regulate the cell cycle, DNA repair, angiogenesis, and other genes that favor cell growth and survival. Because of the mutations, cells with the mutated DNA have evolved to divide without restrictions, hide from the immune system, and develop drug resistance.Back to the Top