@article{9c500117c01f41b38a3e01ad22bfd315,
title = "Aberrant RNA methylation triggers recruitment of an alkylation repair complex",
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.",
keywords = "ASCC, E3 ligase, RNA methylation, RNF113A, alkylation, genome stability, transcription",
author = "Ning Tsao and Brickner, {Joshua R.} and Rebecca Rodell and Adit Ganguly and Matthew Wood and Clement Oyeniran and Tanveer Ahmad and Hua Sun and Albino Bacolla and Lisheng Zhang and Valentina Lukinovi{\'c} and Soll, {Jennifer M.} and Townley, {Brittany A.} and Casanova, {Alexandre G.} and Tainer, {John A.} and Chuan He and Alessandro Vindigni and Nicolas Reynoird and Nima Mosammaparast",
note = "Funding Information: We wish to thank Yang Shi, Hani Zaher, and the Structural Cell Biology of DNA Repair Machines (SBDR) members for their advice on this paper. We acknowledge the Extreme Science and Engineering Discovery Environment (XSEDE; Pittsburgh Supercomputing Center [PSC] allocations TG-BIO160040 and TG-MCB170053 ), which is supported by National Science Foundation (NSF) grant ACI-1548562 . J.A.T. acknowledges support as a Cancer Prevention and Research Institute of Texas (CPRIT) Scholar in Cancer Research and Robert A. Welch Distinguished Chair in Chemistry. This work was supported by Agence Nationale de la Recherche (ANR) ( ANR-16-CE11-0018 to N.R.); Institut National Du Cancer (INCa) ( PLBIO19-021 to N.R.); the NIH Structural Cell Biology of DNA Repair Machines (SBDR) program project ( P01 CA092584 to J.A.T. and N.M.), R01 CA237263 and R01 CA248526 (to A.V.), and R01 CA193318 and R01 CA227001 (to N.M.); the U.S. Department of Defense (DOD) Breast Cancer Research Program (BRCP) Expansion Award ( BC191374 to A.V.); an American Cancer Society Research Scholar Award ( RSG-18-156-01-DMC to N.M.); the Barnard Foundation (to N.M.); and the Alvin J. Siteman Cancer Center Siteman Investment Program (supported by the Foundation for Barnes-Jewish Hospital , Cancer Frontier Fund, to A.V. and N.M.). C.H. is an investigator of the Howard Hughes Medical Institute. Funding Information: We wish to thank Yang Shi, Hani Zaher, and the Structural Cell Biology of DNA Repair Machines (SBDR) members for their advice on this paper. We acknowledge the Extreme Science and Engineering Discovery Environment (XSEDE; Pittsburgh Supercomputing Center [PSC] allocations TG-BIO160040 and TG-MCB170053), which is supported by National Science Foundation (NSF) grant ACI-1548562. J.A.T. acknowledges support as a Cancer Prevention and Research Institute of Texas (CPRIT) Scholar in Cancer Research and Robert A. Welch Distinguished Chair in Chemistry. This work was supported by Agence Nationale de la Recherche (ANR) (ANR-16-CE11-0018 to N.R.); Institut National Du Cancer (INCa) (PLBIO19-021 to N.R.); the NIH Structural Cell Biology of DNA Repair Machines (SBDR) program project (P01 CA092584 to J.A.T. and N.M.), R01 CA237263 and R01 CA248526 (to A.V.), and R01 CA193318 and R01 CA227001 (to N.M.); the U.S. Department of Defense (DOD) Breast Cancer Research Program (BRCP) Expansion Award (BC191374 to A.V.); an American Cancer Society Research Scholar Award (RSG-18-156-01-DMC to N.M.); the Barnard Foundation (to N.M.); and the Alvin J. Siteman Cancer Center Siteman Investment Program (supported by the Foundation for Barnes-Jewish Hospital, Cancer Frontier Fund, to A.V. and N.M.). C.H. is an investigator of the Howard Hughes Medical Institute. N.T. J.R.B. R.R. A.G. M.W. C.O. T.A. V.L. J.M.S. B.A.T. A.G.C. and N.M. carried out cellular and biochemical experiments. H.S. A.B. and L.Z. performed RNA-seq and CLIP-seq bioinformatic analysis. J.A.T. supervised A.B. C.H. supervised L.Z. A.V. supervised M.W. N.R. supervised V.L. T.A. and A.G.C. N.M. supervised the project and wrote the manuscript with N.T. and J.R.B. with input from all other authors. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 The Authors",
year = "2021",
month = oct,
day = "21",
doi = "10.1016/j.molcel.2021.09.024",
language = "English",
volume = "81",
pages = "4228--4242.e8",
journal = "Molecular cell",
issn = "1097-2765",
number = "20",
}