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]
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
editEscherichia 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
editNonsense 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]
References
edit- ^ Nelson, David L.; Cox, Michael M.; Lehninger, Albert L. (2013). Lehninger Principles of Biochemistry (6th ed.). W.H. Freeman. p. 1134. ISBN 978-1-4292-3414-6. OCLC 824794893.
- ^ Hartwell, Leland; Hood, L.; Goldberg, M.; Reynolds, A.; Silver, L.; Veres, R. (2004). Genetics: From Genes to Genomes. McGraw-Hill. p. 267. ISBN 978-0-07-246248-7. OCLC 50417228.
- ^ "Nonsense suppressors". San Diego State University.
- ^ 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.
- ^ Varshney, U.; RajBhandary, U.L. (1990). "Initiation of protein synthesis from a termination codon". Proceedings of the National Academy of Sciences. 87 (4): 1586–90. Bibcode:1990PNAS...87.1586V. doi:10.1073/pnas.87.4.1586. PMC 53520. PMID 2406724.
- ^ 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.
- ^ 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. PMC 6199473. PMID 30181124.
- ^ 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): 343–8. Bibcode:2022Natur.604..343W. doi:10.1038/s41586-022-04533-3. PMC 9446716. PMID 35322228.
- ^ Carter, Barrie J. (2022-06-01). "Suppressing Nonsense for Gene Therapy". Human Gene Therapy. 33 (11–12): 577–8. doi:10.1089/hum.2022.29208.bjc. ISSN 1043-0342. PMID 35537480. S2CID 248695848.
- ^ Stahl FW (October 1995). "The amber mutants of phage T4". Genetics. 141 (2): 439–442. doi:10.1093/genetics/141.2.439. PMC 1206745. PMID 8647382.
- ^ 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.
- ^ Epstein RH, Bolle A, Steinberg CM, Stahl FW (March 2012). "Amber mutants of bacteriophage T4D: their isolation and genetic characterization". Genetics. 190 (3): 831–40. doi:10.1534/genetics.112.138438. PMC 3296251. PMID 22518878.
- ^ Bhattacharya A, Köhrer C, Mandal D, RajBhandary UL (May 2015). "Nonsense suppression in archaea". Proc Natl Acad Sci U S A. 112 (19): 6015–20. Bibcode:2015PNAS..112.6015B. doi:10.1073/pnas.1501558112. PMC 4434778. PMID 25918386.
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