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Antibody cross-reactivity accounts for widespread appearance of m1A in 5’UTRs

Author

Listed:
  • Anya V. Grozhik

    (Weill Cornell Medicine)

  • Anthony O. Olarerin-George

    (Weill Cornell Medicine)

  • Miriam Sindelar

    (Weill Cornell Medicine)

  • Xing Li

    (Weill Cornell Medicine)

  • Steven S. Gross

    (Weill Cornell Medicine)

  • Samie R. Jaffrey

    (Weill Cornell Medicine)

Abstract

N1-methyladenosine (m1A) was proposed to be a highly prevalent modification in mRNA 5’UTRs based on mapping studies using an m1A-binding antibody. We developed a bioinformatic approach to discover m1A and other modifications in mRNA throughout the transcriptome by analyzing preexisting ultra-deep RNA-Seq data for modification-induced misincorporations. Using this approach, we detected appreciable levels of m1A only in one mRNA: the mitochondrial MT-ND5 transcript. As an alternative approach, we also developed an antibody-based m1A-mapping approach to detect m1A at single-nucleotide resolution, and confirmed that the commonly used m1A antibody maps sites to the transcription-start site in mRNA 5’UTRs. However, further analysis revealed that these were false-positives caused by binding of the antibody to the m7G-cap. A different m1A antibody that lacks cap-binding cross-reactivity does not show enriched binding in 5’UTRs. These results demonstrate that high-stoichiometry m1A sites are exceedingly rare in mRNAs and that previous mappings of m1A to 5’UTRs were the result of antibody cross-reactivity to the 5’ cap.

Suggested Citation

  • Anya V. Grozhik & Anthony O. Olarerin-George & Miriam Sindelar & Xing Li & Steven S. Gross & Samie R. Jaffrey, 2019. "Antibody cross-reactivity accounts for widespread appearance of m1A in 5’UTRs," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13146-w
    DOI: 10.1038/s41467-019-13146-w
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    Cited by:

    1. Zhangli Su & Ida Monshaugen & Briana Wilson & Fengbin Wang & Arne Klungland & Rune Ougland & Anindya Dutta, 2022. "TRMT6/61A-dependent base methylation of tRNA-derived fragments regulates gene-silencing activity and the unfolded protein response in bladder cancer," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Belinda Baquero-Pérez & Ivaylo D. Yonchev & Anna Delgado-Tejedor & Rebeca Medina & Mireia Puig-Torrents & Ian Sudbery & Oguzhan Begik & Stuart A. Wilson & Eva Maria Novoa & Juana Díez, 2024. "N6-methyladenosine modification is not a general trait of viral RNA genomes," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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