Nonsense suppressor

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's 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.

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. doi:10.1038/s41586-022-04533-3. ISSN 0028-0836. PMC 9446716.
  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.


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