Bromodomain Protein BRD4 Directs Mitotic Cell Division of Mouse Fibroblasts by Inhibiting DNA Damage

Overview

Journal iScience

Publisher Cell Press

Date 2024 Jul 12

PMID 38993671

Authors

Tiyun Wu

Haitong Hou

Anup Dey

Mahesh Bachu

Xiongfong Chen

Jan Wisniewski

Fuki Kudoh

Chao Chen

Sakshi Chauhan

Hua Xiao

Richard Pan

Keiko Ozato

Affiliations

Soon will be listed here.

Abstract

Bromodomain protein BRD4 binds to acetylated histones to regulate transcription. BRD4 also drives cancer cell proliferation. However, the role of BRD4 in normal cell growth has remained unclear. Here, we investigated this question by using mouse embryonic fibroblasts with conditional Brd4 knockout (KO). We found that Brd4KO cells grow more slowly than wild type cells; they do not complete replication, fail to achieve mitosis, and exhibit extensive DNA damage throughout all cell cycle stages. BRD4 was required for expression of more than 450 cell cycle genes including genes encoding core histones and centromere/kinetochore proteins that are critical for genome replication and chromosomal segregation. Moreover, we show that many genes controlling R-loop formation and DNA damage response (DDR) require BRD4 for expression. Finally, BRD4 constitutively occupied genes controlling R-loop, DDR and cell cycle progression. In summary, BRD4 epigenetically marks above genes and serves as a master regulator of normal cell growth.

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