Nonsense suppressor

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A nonsense suppressor is a factor which can inhibit the effect of the nonsense mutation. Nonsense suppressors can be generally divided into two classes: a) a mutated tRNA which can bind with a termination codon on mRNA; b) a mutation on ribosomes decreasing the effect of a termination codon. It is believed that nonsense suppressors keep a low concentration in the cell and do not disrupt normal translation most of the time. In addition, many genes do not have only one termination codon, and cells commonly use ochre codons as the termination signal, whose nonsense suppressors are usually inefficient. [1] [2] [3]

Contents

Nonsense suppressors are a useful genetic tool, but can also result in problematic side effects, since all identical stop codons in the genome will also be suppressed to the same degree. Genes with different or multiple stop codons will be unaffected.

SUP35, a nonsense suppressor identified by Wickner in 1994, is a prion protein.

In synthetic biology, artificial suppressor elongator tRNAs are used to incorporate unnatural amino acids at nonsense codons placed in the coding sequence of a gene. [4] Start codons can also be suppressed with suppressor initiator tRNAs, such as the amber stop codon suppressor tRNAfMet2(CUA). [5] The amber initiator tRNA is charged with methionine [6] and glutamine. [7]

In recent research, a novel gene therapy approach is provided by Jiaming Wang and Yue Zhang. [8] They use an adeno-associated virus (AAV) vector to deliver a new suppressor tRNA (sup-tRNAtyr) into a mouse model carrying a nonsense mutation(Idua-W401X,TCG→TAG). This model recapitulates a human LSD, mucopolysaccharidosis disease type I (or Hurler Syndrome), caused by absence of the enzyme α-l-iduronidase (IDUA) leading to accumulation of glycosaminoglycans (GAG) and resulting pathogenesis. [9] This method rescues the pathogenic defects and is essentially stable for 6 months.

Bacteriophage T4

Escherichia coli strains carrying nonsense suppressor genes had a central role in the early work on bacteriophage genetics. [10] In particular, E. coli strains carrying amber suppressors (suppressors of the UAG nonsense codon) enabled the isolation and propagation of bacteriophage T4 mutants defective in phage assembly, morphogenesis, DNA replication, DNA repair and genetic recombination and thus facilitated the early study of these processes at a fundamental level. [11] [12]

Archaea

Nonsense suppression by altered tRNA was demonstrated in the archaeon Haloferax volcana for the chain terminating stop codons UAG (amber), UAA (ochre) and UGA (opal). [13]

Related Research Articles

<span class="mw-page-title-main">Genetic code</span> Rules by which information encoded within genetic material is translated into proteins

The genetic code is the set of rules used by living cells to translate information encoded within genetic material into proteins. Translation is accomplished by the ribosome, which links proteinogenic amino acids in an order specified by messenger RNA (mRNA), using transfer RNA (tRNA) molecules to carry amino acids and to read the mRNA three nucleotides at a time. The genetic code is highly similar among all organisms and can be expressed in a simple table with 64 entries.

<span class="mw-page-title-main">Stop codon</span> Codon that marks the end of a protein-coding sequence

In molecular biology, a stop codon is a codon that signals the termination of the translation process of the current protein. Most codons in messenger RNA correspond to the addition of an amino acid to a growing polypeptide chain, which may ultimately become a protein; stop codons signal the termination of this process by binding release factors, which cause the ribosomal subunits to disassociate, releasing the amino acid chain.

In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a nonsense codon, or a premature stop codon in the transcribed mRNA, and leads to a truncated, incomplete, and possibly nonfunctional protein product. Nonsense mutations are not always harmful; the functional effect of a nonsense mutation depends on many aspects, such as the location of the stop codon within the coding DNA. For example, the effect of a nonsense mutation depends on the proximity of the nonsense mutation to the original stop codon, and the degree to which functional subdomains of the protein are affected. As nonsense mutations leads to premature termination of polypeptide chains; they are also called chain termination mutations.

<i>Escherichia virus T4</i> Species of bacteriophage

Escherichia virus T4 is a species of bacteriophages that infect Escherichia coli bacteria. It is a double-stranded DNA virus in the subfamily Tevenvirinae from the family Myoviridae. T4 is capable of undergoing only a lytic life cycle and not the lysogenic life cycle. The species was formerly named T-even bacteriophage, a name which also encompasses, among other strains, Enterobacteria phage T2, Enterobacteria phage T4 and Enterobacteria phage T6.

The Shine–Dalgarno (SD) sequence is a ribosomal binding site in bacterial and archaeal messenger RNA, generally located around 8 bases upstream of the start codon AUG. The RNA sequence helps recruit the ribosome to the messenger RNA (mRNA) to initiate protein synthesis by aligning the ribosome with the start codon. Once recruited, tRNA may add amino acids in sequence as dictated by the codons, moving downstream from the translational start site.

Genetics, a discipline of biology, is the science of heredity and variation in living organisms.

Complementation refers to a genetic process when two strains of an organism with different homozygous recessive mutations that produce the same mutant phenotype have offspring that express the wild-type phenotype when mated or crossed. Complementation will ordinarily occur if the mutations are in different genes. Complementation may also occur if the two mutations are at different sites within the same gene, but this effect is usually weaker than that of intergenic complementation. When the mutations are in different genes, each strain's genome supplies the wild-type allele to "complement" the mutated allele of the other strain's genome. Since the mutations are recessive, the offspring will display the wild-type phenotype. A complementation test can test whether the mutations in two strains are in different genes. Complementation is usually weaker or absent if the mutations are in the same gene. The convenience and essence of this test is that the mutations that produce a phenotype can be assigned to different genes without the exact knowledge of what the gene product is doing on a molecular level. American geneticist Edward B. Lewis developed the complementation test.

<span class="mw-page-title-main">Start codon</span> First codon of a messenger RNA translated by a ribosome

The start codon is the first codon of a messenger RNA (mRNA) transcript translated by a ribosome. The start codon always codes for methionine in eukaryotes and archaea and a N-formylmethionine (fMet) in bacteria, mitochondria and plastids.

<span class="mw-page-title-main">Nonsense-mediated decay</span> Elimination of mRNA with premature stop codons in eukaryotes

Nonsense-mediated mRNA decay (NMD) is a surveillance pathway that exists in all eukaryotes. Its main function is to reduce errors in gene expression by eliminating mRNA transcripts that contain premature stop codons. Translation of these aberrant mRNAs could, in some cases, lead to deleterious gain-of-function or dominant-negative activity of the resulting proteins.

<span class="mw-page-title-main">Gene</span> Sequence of DNA or RNA that codes for an RNA or protein product

In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA, that is transcribed to produce a functional RNA. There are two types of molecular genes: protein-coding genes and non-coding genes.

A suppressor mutation is a second mutation that alleviates or reverts the phenotypic effects of an already existing mutation in a process defined synthetic rescue. Genetic suppression therefore restores the phenotype seen prior to the original background mutation. Suppressor mutations are useful for identifying new genetic sites which affect a biological process of interest. They also provide evidence between functionally interacting molecules and intersecting biological pathways.

Temperature-sensitive mutants are variants of genes that allow normal function of the organism at low temperatures, but altered function at higher temperatures. Cold sensitive mutants are variants of genes that allow normal function of the organism at higher temperatures, but altered function at low temperatures.

Lethal alleles are alleles that cause the death of the organism that carries them. They are usually a result of mutations in genes that are essential for growth or development. Lethal alleles may be recessive, dominant, or conditional depending on the gene or genes involved.

The phage group was an informal network of biologists centered on Max Delbrück that contributed heavily to bacterial genetics and the origins of molecular biology in the mid-20th century. The phage group takes its name from bacteriophages, the bacteria-infecting viruses that the group used as experimental model organisms. In addition to Delbrück, important scientists associated with the phage group include: Salvador Luria, Alfred Hershey, Seymour Benzer, Charles Steinberg, Gunther Stent, James D. Watson, Frank Stahl, and Renato Dulbecco.

Synthetic rescue refers to a genetic interaction in which a cell that is nonviable, sensitive to a specific drug, or otherwise impaired due to the presence of a genetic mutation becomes viable when the original mutation is combined with a second mutation in a different gene. The second mutation can either be a loss-of-function mutation or a gain-of-function mutation.

mRNA surveillance mechanisms are pathways utilized by organisms to ensure fidelity and quality of messenger RNA (mRNA) molecules. There are a number of surveillance mechanisms present within cells. These mechanisms function at various steps of the mRNA biogenesis pathway to detect and degrade transcripts that have not properly been processed.

<span class="mw-page-title-main">DNA and RNA codon tables</span> List of standard rules to translate DNA encoded information into proteins

A codon table can be used to translate a genetic code into a sequence of amino acids. The standard genetic code is traditionally represented as an RNA codon table, because when proteins are made in a cell by ribosomes, it is messenger RNA (mRNA) that directs protein synthesis. The mRNA sequence is determined by the sequence of genomic DNA. In this context, the standard genetic code is referred to as translation table 1. It can also be represented in a DNA codon table. The DNA codons in such tables occur on the sense DNA strand and are arranged in a 5′-to-3′ direction. Different tables with alternate codons are used depending on the source of the genetic code, such as from a cell nucleus, mitochondrion, plastid, or hydrogenosome.

<span class="mw-page-title-main">Fred Sherman (scientist)</span> American geneticist

Fred Sherman was an American scientist who pioneered the use of the budding yeast Saccharomyces cerevisiae as a model for studying the genetics, molecular biology, and biochemistry of eukaryotic cells. His research encompassed broad areas of yeast biology including gene expression, protein synthesis, messenger RNA processing, bioenergetics, and mechanisms of mutagenesis. He also contributed extensively to the genetics of the opportunistic pathogen Candida albicans.

<span class="mw-page-title-main">Epistasis</span> Dependence of a gene mutations phenotype on mutations in other genes

Epistasis is a phenomenon in genetics in which the effect of a gene mutation is dependent on the presence or absence of mutations in one or more other genes, respectively termed modifier genes. In other words, the effect of the mutation is dependent on the genetic background in which it appears. Epistatic mutations therefore have different effects on their own than when they occur together. Originally, the term epistasis specifically meant that the effect of a gene variant is masked by that of different gene.

Charles 'Charley' M. Steinberg was an immunobiologist and permanent member of the Basel Institute for Immunology. He was a former student of Max Delbrück. Notably he hosted Richard Feynman at Caltech when Feynman studied molecular biology, leading Feynman to remark that Charlie was “...the smartest guy I know”. He was instrumental in the discovery of V(D)J recombination, bacteriophage genetics as part of the phage group and co-discoverer of the amber-mutant of the T4 bacteriophage that led to the recognition of stop codons.

References

  1. ↑ David L. Nelson; et al. (2013). Principles of Biochemistry (vol. 3). New York, NY: W. H. Freeman and Company. p. 1134. ISBN   978-1-4292-3414-6.
  2. ↑ Hartwell, Leland; L. Hood; M. Goldberg; A. Reynolds; L. Silver; R. Veres (2004). Genetics: From Genes to Genomes. New York, NY: McGraw-Hill. p. 267. ISBN   978-0-07-246248-7.
  3. ↑ "Nonsense suppressors". San Diego State University.
  4. ↑ Young, Douglas D; Schultz, Peter G (2018). "Playing with the Molecules of Life". ACS Chemical Biology. 13 (4): 854–870. doi:10.1021/acschembio.7b00974. PMC   6061972 . PMID   29345901.
  5. ↑ Varshney, U.; RajBhandary, U. L. (1990-02-01). "Initiation of protein synthesis from a termination codon". Proceedings of the National Academy of Sciences. 87 (4): 1586–1590. Bibcode:1990PNAS...87.1586V. doi: 10.1073/pnas.87.4.1586 . ISSN   0027-8424. PMC   53520 . PMID   2406724.
  6. ↑ Vincent, Russel M.; Wright, Bradley W.; Jaschke, Paul R. (2019-03-11). "Measuring Amber Initiator tRNA Orthogonality in a Genomically Recoded Organism". ACS Synthetic Biology. 8 (4): 675–685. doi:10.1021/acssynbio.9b00021. PMID   30856316. S2CID   75136654.
  7. ↑ Govindan, Ashwin; Miryala, Sandeep; Mondal, Sanjay; Varshney, Umesh (2018-09-04). "Development of Assay Systems for Amber Codon Decoding at the Steps of Initiation and Elongation in Mycobacteria". Journal of Bacteriology. 200 (22). doi:10.1128/jb.00372-18. ISSN   0021-9193. PMC   6199473 . PMID   30181124.
  8. ↑ Wang, Jiaming; Zhang, Yue; Mendonca, Craig A.; Yukselen, Onur; Muneeruddin, Khaja; Ren, Lingzhi; Liang, Jialing; Zhou, Chen; Xie, Jun; Li, Jia; Jiang, Zhong; Kucukural, Alper; Shaffer, Scott A.; Gao, Guangping; Wang, Dan (2022-04-14). "AAV-delivered suppressor tRNA overcomes a nonsense mutation in mice". Nature. 604 (7905): 343–348. Bibcode:2022Natur.604..343W. doi:10.1038/s41586-022-04533-3. ISSN   0028-0836. PMC   9446716 . PMID   35322228.
  9. ↑ Carter, Barrie J. (2022-06-01). "Suppressing Nonsense for Gene Therapy". Human Gene Therapy. 33 (11–12): 577–578. doi:10.1089/hum.2022.29208.bjc. ISSN   1043-0342. PMID   35537480. S2CID   248695848.
  10. ↑ Stahl FW. The amber mutants of phage T4. Genetics. 1995 Oct;141(2):439-42. doi: 10.1093/genetics/141.2.439. PMID 8647382; PMCID: PMC1206745
  11. ↑ Epstein RH, Bolle A, Steinberg CM, Kellenberger E, Boy de la Tour E, Chevalley R, Edgar RS, Susman M, Denhardt GH, Lielausis A (1963). "Physiological Studies of Conditional Lethal Mutants of Bacteriophage T4D". Cold Spring Harbor Symposia on Quantitative Biology. 28: 375–394. doi:10.1101/SQB.1963.028.01.053. ISSN 0091-7451
  12. ↑ Epstein RH, Bolle A, Steinberg CM, Stahl FW. Amber mutants of bacteriophage T4D: their isolation and genetic characterization. Genetics. 2012 Mar;190(3):831-40. doi: 10.1534/genetics.112.138438. PMID 22518878
  13. ↑ Bhattacharya A, Köhrer C, Mandal D, RajBhandary UL. Nonsense suppression in archaea. Proc Natl Acad Sci U S A. 2015 May 12;112(19):6015-20. doi: 10.1073/pnas.1501558112. Epub 2015 Apr 27. PMID 25918386; PMCID: PMC4434778


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