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Ch. 14 - Translation and Proteins
Klug - Concepts of Genetics 12th Edition
Klug12th EditionConcepts of Genetics ISBN: 9780135564776Not the one you use?Change textbook
All textbooksKlug 12th EditionCh. 14 - Translation and ProteinsProblem 36b
Chapter 14, Problem 36b

The flow of genetic information from DNA to protein is mediated by messenger RNA. If you introduce short DNA strands (called antisense oligonucleotides) that are complementary to mRNAs, hydrogen bonding may occur and 'label' the DNA/RNA hybrid for ribonuclease-H degradation of the RNA. One study [Lloyd et al. (2001). Nucl. Acids Res. 29:3664–3673] compared the effect of different-length antisense oligonucleotides upon ribonuclease-H–mediated degradation of tumor necrosis factor (TNFα) mRNA. TNFα exhibits antitumor and pro-inflammatory activities. The following graph indicates the efficacy of various-sized antisense oligonucleotides in causing ribonuclease-H cleavage. What general conclusion can be drawn from the graph?

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1
Examine the graph provided in the problem to identify the relationship between the length of the antisense oligonucleotides and their efficacy in causing ribonuclease-H cleavage of TNFα mRNA.
Note the trend in the graph: Does the efficacy increase, decrease, or remain constant as the length of the antisense oligonucleotides changes? Pay attention to any specific lengths that show a peak or drop in efficacy.
Consider the biological implications of the observed trend. For example, longer antisense oligonucleotides may form more stable hybrids with mRNA, but they may also be more prone to degradation or less specific in binding.
Relate the observed trend to the mechanism of ribonuclease-H activity. Ribonuclease-H cleaves RNA in DNA/RNA hybrids, so the stability and specificity of the hybrid are critical for effective cleavage.
Formulate a general conclusion based on the graph. For instance, you might conclude that there is an optimal length for antisense oligonucleotides that balances stability, specificity, and susceptibility to ribonuclease-H cleavage, leading to maximum efficacy.

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Key Concepts

Here are the essential concepts you must grasp in order to answer the question correctly.

Gene Expression

Gene expression is the process by which information from a gene is used to synthesize a functional gene product, typically proteins. This involves two main steps: transcription, where DNA is transcribed into messenger RNA (mRNA), and translation, where mRNA is translated into a protein. Understanding this process is crucial for analyzing how antisense oligonucleotides can interfere with mRNA and affect protein synthesis.
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Antisense Oligonucleotides

Antisense oligonucleotides are short, single-stranded DNA or RNA molecules designed to bind to specific mRNA sequences. By hybridizing with mRNA, they can block translation or promote degradation of the mRNA through mechanisms such as ribonuclease-H activity. This targeted approach is used in research and therapeutic applications to modulate gene expression, particularly in diseases like cancer.
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Ribonuclease-H Activity

Ribonuclease-H (RNase H) is an enzyme that degrades the RNA strand of RNA-DNA hybrids. When antisense oligonucleotides bind to their complementary mRNA, RNase H can recognize and cleave the RNA, leading to reduced levels of the target mRNA. Understanding the role of RNase H is essential for interpreting the effectiveness of different-length antisense oligonucleotides in degrading specific mRNAs, such as TNFα in the context of inflammation and cancer.
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Related Practice
Textbook Question

Deep in a previously unexplored South American rain forest, a plant species was discovered with true-breeding varieties whose flowers were pink, rose, orange, or purple. A very astute plant geneticist made a single cross, carried to the F₂ generation, as shown:

P₁: purple × pink

F₁: all purple

F₂: 27/64 purple 16/64 pink 12/64 rose 9/64 orange

Based solely on these data, he proposed both a mode of inheritance for flower pigmentation and a biochemical pathway for the synthesis of these pigments. Carefully study the data. Create a hypothesis of your own to explain the mode of inheritance. Then propose a biochemical pathway consistent with your hypothesis. How could you test the hypothesis by making other crosses?

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Textbook Question

Many antibiotics are effective as drugs to fight off bacterial infections because they inhibit protein synthesis in bacterial cells. Using the information provided in the following table that highlights several antibiotics and their mode of action, discuss which phase of translation is inhibited: initiation, elongation, or termination. What other components of the translational machinery could be targeted to inhibit bacterial protein synthesis?

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Textbook Question

The flow of genetic information from DNA to protein is mediated by messenger RNA. If you introduce short DNA strands (called antisense oligonucleotides) that are complementary to mRNAs, hydrogen bonding may occur and 'label' the DNA/RNA hybrid for ribonuclease-H degradation of the RNA. One study [Lloyd et al. (2001). Nucl. Acids Res. 29:3664–3673] compared the effect of different-length antisense oligonucleotides upon ribonuclease-H–mediated degradation of tumor necrosis factor (TNFα) mRNA. TNFα exhibits antitumor and pro-inflammatory activities. The following graph indicates the efficacy of various-sized antisense oligonucleotides in causing ribonuclease-H cleavage. Describe how antisense oligonucleotides interrupt the flow of genetic information in a cell.

1212
views
Textbook Question

The flow of genetic information from DNA to protein is mediated by messenger RNA. If you introduce short DNA strands (called antisense oligonucleotides) that are complementary to mRNAs, hydrogen bonding may occur and 'label' the DNA/RNA hybrid for ribonuclease-H degradation of the RNA. One study [Lloyd et al. (2001). Nucl. Acids Res. 29:3664–3673] compared the effect of different-length antisense oligonucleotides upon ribonuclease-H–mediated degradation of tumor necrosis factor (TNFα) mRNA. TNFα exhibits antitumor and pro-inflammatory activities. The following graph indicates the efficacy of various-sized antisense oligonucleotides in causing ribonuclease-H cleavage. What factors other than oligonucleotide length are likely to influence antisense efficacy in vivo?

662
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Textbook Question

Infantile cardiomyopathy is a devastating disorder that is fatal during the first year of life due to defects in the function of heart muscles resulting from mitochondrial dysfunction. A study, performed by Götz et al. [(2011). Am. J. Hum. Genet. 88:635–642), identified two different causative mutations in the gene for mitochondrial alanyl-tRNA synthetase (mtAlaRS). One mutation changes a leucine residue at amino acid position 155 to arginine (p.Leu155Arg). The other mutation changes arginine at position 592 to tryptophan (p.Arg592Trp). The mtAlaRS enzyme has an N-terminal domain (amino acids 36–481) that catalyzes tRNA aminoacylation and an internal editing domain (amino acids 484–782) that catalyzes deacylation in the case that the tRNA is charged with the wrong amino acid.

Consider the position of the disease causing missense mutations in the mtAlaRS gene in the context of the known protein domains of this enzyme. What predictions can you make about how these mutations impair protein synthesis within mitochondria in different ways?

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Textbook Question

Infantile cardiomyopathy is a devastating disorder that is fatal during the first year of life due to defects in the function of heart muscles resulting from mitochondrial dysfunction. A study, performed by Götz et al. [(2011). Am. J. Hum. Genet. 88:635–642), identified two different causative mutations in the gene for mitochondrial alanyl-tRNA synthetase (mtAlaRS). One mutation changes a leucine residue at amino acid position 155 to arginine (p.Leu155Arg). The other mutation changes arginine at position 592 to tryptophan (p.Arg592Trp). The mtAlaRS enzyme has an N-terminal domain (amino acids 36–481) that catalyzes tRNA aminoacylation and an internal editing domain (amino acids 484–782) that catalyzes deacylation in the case that the tRNA is charged with the wrong amino acid.

Which mutation would you predict has a more severe impairment of translation in mitochondria, and why?

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