IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-46703-z.html
   My bibliography  Save this article

Extended stop codon context predicts nonsense codon readthrough efficiency in human cells

Author

Listed:
  • Kotchaphorn Mangkalaphiban

    (UMass Chan Medical School
    UMass Chan Medical School)

  • Lianwu Fu

    (The University of Alabama at Birmingham)

  • Ming Du

    (The University of Alabama at Birmingham)

  • Kari Thrasher

    (The University of Alabama at Birmingham)

  • Kim M. Keeling

    (The University of Alabama at Birmingham)

  • David M. Bedwell

    (The University of Alabama at Birmingham)

  • Allan Jacobson

    (UMass Chan Medical School)

Abstract

Protein synthesis terminates when a stop codon enters the ribosome’s A-site. Although termination is efficient, stop codon readthrough can occur when a near-cognate tRNA outcompetes release factors during decoding. Seeking to understand readthrough regulation we used a machine learning approach to analyze readthrough efficiency data from published HEK293T ribosome profiling experiments and compared it to comparable yeast experiments. We obtained evidence for the conservation of identities of the stop codon, its context, and 3’-UTR length (when termination is compromised), but not the P-site codon, suggesting a P-site tRNA role in readthrough regulation. Models trained on data from cells treated with the readthrough-promoting drug, G418, accurately predicted readthrough of premature termination codons arising from CFTR nonsense alleles that cause cystic fibrosis. This predictive ability has the potential to aid development of nonsense suppression therapies by predicting a patient’s likelihood of improvement in response to drugs given their nonsense mutation sequence context.

Suggested Citation

  • Kotchaphorn Mangkalaphiban & Lianwu Fu & Ming Du & Kari Thrasher & Kim M. Keeling & David M. Bedwell & Allan Jacobson, 2024. "Extended stop codon context predicts nonsense codon readthrough efficiency in human cells," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46703-z
    DOI: 10.1038/s41467-024-46703-z
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-46703-z
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-024-46703-z?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Ellen M. Welch & Elisabeth R. Barton & Jin Zhuo & Yuki Tomizawa & Westley J. Friesen & Panayiota Trifillis & Sergey Paushkin & Meenal Patel & Christopher R. Trotta & Seongwoo Hwang & Richard G. Wilde , 2007. "PTC124 targets genetic disorders caused by nonsense mutations," Nature, Nature, vol. 447(7140), pages 87-91, May.
    2. Ambar Kachale & Zuzana Pavlíková & Anna Nenarokova & Adriana Roithová & Ignacio M. Durante & Petra Miletínová & Kristína Záhonová & Serafim Nenarokov & Jan Votýpka & Eva Horáková & Robert L. Ross & Vy, 2023. "Short tRNA anticodon stem and mutant eRF1 allow stop codon reassignment," Nature, Nature, vol. 613(7945), pages 751-758, January.
    3. Zhenyu Xu & Wu Wei & Julien Gagneur & Fabiana Perocchi & Sandra Clauder-Münster & Jurgi Camblong & Elisa Guffanti & Françoise Stutz & Wolfgang Huber & Lars M. Steinmetz, 2009. "Bidirectional promoters generate pervasive transcription in yeast," Nature, Nature, vol. 457(7232), pages 1033-1037, February.
    4. Ambar Kachale & Zuzana Pavlíková & Anna Nenarokova & Adriana Roithová & Ignacio M. Durante & Petra Miletínová & Kristína Záhonová & Serafim Nenarokov & Jan Votýpka & Eva Horáková & Robert L. Ross & Vy, 2023. "Author Correction: Short tRNA anticodon stem and mutant eRF1 allow stop codon reassignment," Nature, Nature, vol. 618(7965), pages 23-23, June.
    5. Alan Brown & Sichen Shao & Jason Murray & Ramanujan S. Hegde & V. Ramakrishnan, 2015. "Structural basis for stop codon recognition in eukaryotes," Nature, Nature, vol. 524(7566), pages 493-496, August.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Maria Luisa Romero Romero & Jonas Poehls & Anastasiia Kirilenko & Doris Richter & Tobias Jumel & Anna Shevchenko & Agnes Toth-Petroczy, 2024. "Environment modulates protein heterogeneity through transcriptional and translational stop codon readthrough," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Franziska Nadler & Elena Lavdovskaia & Angelique Krempler & Luis Daniel Cruz-Zaragoza & Sven Dennerlein & Ricarda Richter-Dennerlein, 2022. "Human mtRF1 terminates COX1 translation and its ablation induces mitochondrial ribosome-associated quality control," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    3. Bingnan Li & Patrice Zeis & Yujie Zhang & Alisa Alekseenko & Eliska Fürst & Yerma Pareja Sanchez & Gen Lin & Manu M. Tekkedil & Ilaria Piazza & Lars M. Steinmetz & Vicent Pelechano, 2023. "Differential regulation of mRNA stability modulates transcriptional memory and facilitates environmental adaptation," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    4. Komal Soni & Anusree Sivadas & Attila Horvath & Nikolay Dobrev & Rippei Hayashi & Leo Kiss & Bernd Simon & Klemens Wild & Irmgard Sinning & Tamás Fischer, 2023. "Mechanistic insights into RNA surveillance by the canonical poly(A) polymerase Pla1 of the MTREC complex," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    5. Nikhil Bharti & Leonardo Santos & Marcos Davyt & Stine Behrmann & Marie Eichholtz & Alejandro Jimenez-Sanchez & Jeong S. Hong & Andras Rab & Eric J. Sorscher & Suki Albers & Zoya Ignatova, 2024. "Translation velocity determines the efficacy of engineered suppressor tRNAs on pathogenic nonsense mutations," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    6. Shijie Huang & Arpan Bhattacharya & Mikel D. Ghelfi & Hong Li & Clark Fritsch & David M. Chenoweth & Yale E. Goldman & Barry S. Cooperman, 2022. "Ataluren binds to multiple protein synthesis apparatus sites and competitively inhibits release factor-dependent termination," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    7. Ramona Weber & Leon Kleemann & Insa Hirschberg & Min-Yi Chung & Eugene Valkov & Cátia Igreja, 2022. "DAP5 enables main ORF translation on mRNAs with structured and uORF-containing 5′ leaders," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    8. Charlotte Cautereels & Jolien Smets & Peter Bircham & Dries De Ruysscher & Anna Zimmermann & Peter De Rijk & Jan Steensels & Anton Gorkovskiy & Joleen Masschelein & Kevin J. Verstrepen, 2024. "Combinatorial optimization of gene expression through recombinase-mediated promoter and terminator shuffling in yeast," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    9. Haiqing Xu & Chuan Li & Chuan Xu & Jianzhi Zhang, 2023. "Chance promoter activities illuminate the origins of eukaryotic intergenic transcriptions," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    10. Reiner-Benaim Anat & Davis Ronald W. & Juneau Kara, 2014. "Scan statistics analysis for detection of introns in time-course tiling array data," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 13(2), pages 173-190, April.
    11. Ying Xiong & Weijing Han & Chunhua Xu & Jing Shi & Lisha Wang & Taoli Jin & Qi Jia & Ying Lu & Shuxin Hu & Shuo-Xing Dou & Wei Lin & Terence R. Strick & Shuang Wang & Ming Li, 2024. "Single-molecule reconstruction of eukaryotic factor-dependent transcription termination," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    12. Jan Zrimec & Xiaozhi Fu & Azam Sheikh Muhammad & Christos Skrekas & Vykintas Jauniskis & Nora K. Speicher & Christoph S. Börlin & Vilhelm Verendel & Morteza Haghir Chehreghani & Devdatt Dubhashi & Ver, 2022. "Controlling gene expression with deep generative design of regulatory DNA," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46703-z. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.