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Nonsense suppressor

January 01, 1970

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 edit

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 edit

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]

References edit

  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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January 01, 1970
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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 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 a 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 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 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 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 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 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 ISSN 0021 9193 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 343 348 Bibcode 2022Natur 604 343W doi 10 1038 s41586 022 04533 3 ISSN 0028 0836 PMC 9446716 PMID 35322228 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 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 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 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 Bhattacharya A Kohrer 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 nbsp This genetics article is a stub You can help Wikipedia by expanding it vte Retrieved from https en wikipedia org w index php title Nonsense suppressor amp oldid 1217450160, wikipedia, wiki, book, books, library,

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