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Tsao N, Brickner JR, Rodell R, et al. Aberrant RNA methylation triggers recruitment of an alkylation repair complex. Mol Cell. 2021;81(20):4228-4242.e8doi: 10.1016/j.molcel.2021.09.024.
Tsao, N., Brickner, J. R., Rodell, R., Ganguly, A., Wood, M., Oyeniran, C., Ahmad, T., Sun, H., Bacolla, A., Zhang, L., Lukinović, V., Soll, J. M., Townley, B. A., Casanova, A. G., Tainer, J. A., He, C., Vindigni, A., Reynoird, N., & Mosammaparast, N. (2021). Aberrant RNA methylation triggers recruitment of an alkylation repair complex. Molecular cell, 81(20), 4228-4242.e8. https://doi.org/10.1016/j.molcel.2021.09.024
Tsao, Ning, et al. "Aberrant RNA methylation triggers recruitment of an alkylation repair complex." Molecular cell vol. 81,20 (2021): 4228-4242.e8. doi: https://doi.org/10.1016/j.molcel.2021.09.024
Tsao N, Brickner JR, Rodell R, Ganguly A, Wood M, Oyeniran C, Ahmad T, Sun H, Bacolla A, Zhang L, Lukinović V, Soll JM, Townley BA, Casanova AG, Tainer JA, He C, Vindigni A, Reynoird N, Mosammaparast N. Aberrant RNA methylation triggers recruitment of an alkylation repair complex. Mol Cell. 2021 Oct 21;81(20):4228-4242.e8. doi: 10.1016/j.molcel.2021.09.024. PMID: 34686315.
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Mol Cell. 2021 Oct 21;81(20):4228-4242.e8. doi: 10.1016/j.molcel.2021.09.024.

Aberrant RNA methylation triggers recruitment of an alkylation repair complex.

Molecular cell

Ning Tsao, Joshua R Brickner, Rebecca Rodell, Adit Ganguly, Matthew Wood, Clement Oyeniran, Tanveer Ahmad, Hua Sun, Albino Bacolla, Lisheng Zhang, Valentina Lukinović, Jennifer M Soll, Brittany A Townley, Alexandre G Casanova, John A Tainer, Chuan He, Alessandro Vindigni, Nicolas Reynoird, Nima Mosammaparast

Affiliations

  1. Department of Pathology & Immunology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA.
  2. Division of Oncology, Department of Medicine, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA; Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
  3. Institute for Advanced Biosciences, Grenoble Alpes University, CNRS UMR5309, INSERM U1209, Grenoble, France.
  4. Department of Molecular and Cellular Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
  5. Department of Biochemistry and Molecular Biology, Department of Chemistry, and Institute for Biophysical Dynamics, University of Chicago, Chicago IL 60637, USA.
  6. Department of Molecular and Cellular Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA; Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
  7. Department of Biochemistry and Molecular Biology, Department of Chemistry, and Institute for Biophysical Dynamics, University of Chicago, Chicago IL 60637, USA; Howard Hughes Medical Institute, University of Chicago, Chicago IL 60637, USA.
  8. Division of Oncology, Department of Medicine, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA.
  9. Department of Pathology & Immunology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA. Electronic address: [email protected].

PMID: 34686315 DOI: 10.1016/j.molcel.2021.09.024

Abstract

Central to genotoxic responses is their ability to sense highly specific signals to activate the appropriate repair response. We previously reported that the activation of the ASCC-ALKBH3 repair pathway is exquisitely specific to alkylation damage in human cells. Yet the mechanistic basis for the selectivity of this pathway was not immediately obvious. Here, we demonstrate that RNA but not DNA alkylation is the initiating signal for this process. Aberrantly methylated RNA is sufficient to recruit ASCC, while an RNA dealkylase suppresses ASCC recruitment during chemical alkylation. In turn, recruitment of ASCC during alkylation damage, which is mediated by the E3 ubiquitin ligase RNF113A, suppresses transcription and R-loop formation. We further show that alkylated pre-mRNA is sufficient to activate RNF113A E3 ligase in vitro in a manner dependent on its RNA binding Zn-finger domain. Together, our work identifies an unexpected role for RNA damage in eliciting a specific response to genotoxins.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Keywords: ASCC; E3 ligase; RNA methylation; RNF113A; alkylation; genome stability; transcription

Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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