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

Liu Liu; Baicheng Lin; Shasha Yin; Lauren E. Ball; Joe R. Delaney; David T. Long; Wenjian Gan

doi:10.1126/sciadv.add8928

journal article Dec 09, 2022

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

Liu Liu

Baicheng Lin Shasha Yin Lauren E. Ball Joe R. Delaney

David T. Long

Wenjian Gan

Science Advances Vol. 8 No. 49 · American Association for the Advancement of Science (AAAS)

View at Publisher Save 10.1126/sciadv.add8928

Abstract

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.

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Details

Published: Dec 09, 2022
Vol/Issue: 8(49)

Authors

L

Liu Liu