DDX21 mediates co-transcriptional RNA m6A modification to promote transcription termination and genome stability

  • Mol Cell. 2024 May 2;84(9):1711-1726.e11. doi: 10.1016/j.molcel.2024.03.006.
Jin-Dong Hao  1 ,  Qian-Lan Liu  2 ,  Meng-Xia Liu  3 ,  Xing Yang  1 ,  Liu-Ming Wang  1 ,  Si-Yi Su  4 ,  Wen Xiao  1 ,  Meng-Qi Zhang  1 ,  Yi-Chang Zhang  1 ,  Lan Zhang  3 ,  Yu-Sheng Chen  5 ,  Yun-Gui Yang  6 ,  Jie Ren  7
Affiliations
  • 1. Key Laboratory of RNA Science and Engineering, CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 2. Key Laboratory of RNA Science and Engineering, CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: [email protected].
  • 3. Key Laboratory of RNA Science and Engineering, CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Sino-Danish College, University of Chinese Academy of Sciences, Beijing 101408, China.
  • 4. Key Laboratory of RNA Science and Engineering, CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Future Technology, University of Chinese Academy of Sciences, Beijing 100049, China.
  • 5. Key Laboratory of RNA Science and Engineering, CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China.
  • 6. Key Laboratory of RNA Science and Engineering, CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: [email protected].
  • 7. Key Laboratory of RNA Science and Engineering, CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Sino-Danish College, University of Chinese Academy of Sciences, Beijing 101408, China; School of Future Technology, University of Chinese Academy of Sciences, Beijing 100049, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: [email protected].
PMID: 38569554 DOI: 10.1016/j.molcel.2024.03.006
Abstract

N6-methyladenosine (m6A) is a crucial RNA modification that regulates diverse biological processes in human cells, but its co-transcriptional deposition and functions remain poorly understood. Here, we identified the RNA helicase DDX21 with a previously unrecognized role in directing m6A modification on nascent RNA for co-transcriptional regulation. DDX21 interacts with METTL3 for co-recruitment to chromatin through its recognition of R-loops, which can be formed co-transcriptionally as nascent transcripts hybridize onto the template DNA strand. Moreover, DDX21's helicase activity is needed for METTL3-mediated m6A deposition onto nascent RNA following recruitment. At transcription termination regions, this nexus of actions promotes XRN2-mediated termination of RNAPII transcription. Disruption of any of these steps, including the loss of DDX21, METTL3, or their enzymatic activities, leads to defective termination that can induce DNA damage. Therefore, we propose that the R-loop-DDX21-METTL3 nexus forges the missing link for co-transcriptional modification of m6A, coordinating transcription termination and genome stability.

Keywords
DDX21; DNA damage; METTL3; R-loops; RNA m(6)A methylation; XRN2; co-transcriptional regulation; genome stability; transcription termination; transcription-replication collisions.
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