Arginine methylation of BRD4 by PRMT2/4 governs transcription and DNA repair

Sci Adv. 2022 Dec 9;8(49):eadd8928. doi: 10.1126/sciadv.add8928. Epub 2022 Dec 7.


BRD4 functions as an epigenetic reader and plays a crucial role in regulating transcription and genome stability. Dysregulation of BRD4 is frequently observed in various human cancers. However, the molecular details of BRD4 regulation remain largely unknown. Here, we report that PRMT2- and PRMT4-mediated arginine methylation is pivotal for BRD4 functions on transcription, DNA repair, and tumor growth. Specifically, PRMT2/4 interacts with and methylates BRD4 at R179, R181, and R183. This arginine methylation selectively controls a transcriptional program by promoting BRD4 recruitment to acetylated histones/chromatin. Moreover, BRD4 arginine methylation is induced by DNA damage and thereby promotes its binding to chromatin for DNA repair. Deficiency in BRD4 arginine methylation significantly suppresses tumor growth and sensitizes cells to BET inhibitors and DNA damaging agents. Therefore, our findings reveal an arginine methylation-dependent regulatory mechanism of BRD4 and highlight targeting PRMT2/4 for better antitumor effect of BET inhibitors and DNA damaging agents.

MeSH terms

  • Arginine
  • Cell Cycle Proteins / genetics
  • Chromatin
  • DNA
  • DNA Repair
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Neoplasms*
  • Nuclear Proteins* / genetics
  • Protein-Arginine N-Methyltransferases / genetics
  • Transcription Factors / genetics


  • Nuclear Proteins
  • Arginine
  • Transcription Factors
  • DNA
  • Chromatin
  • PRMT2 protein, human
  • Protein-Arginine N-Methyltransferases
  • Intracellular Signaling Peptides and Proteins
  • BRD4 protein, human
  • Cell Cycle Proteins