Bromodomain protein BRD4 directs mitotic cell division of mouse fibroblasts by inhibiting DNA damage

Author:

Wu, Tiyun

Hou, Haitong

Dey, Anup

Bachu, Mahesh

Chen,Jack

Wisniewski, Jan

Kudoh, Fuki

Chen, Chao

Chauhan, Sakshi

Xiao, Hua

Pan, Richard

Ozato, Keiko
Author Address

Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA., Science Center for Future Foods, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China., Weill Cornell Medicine, Graduate School of Medical Sciences, 1300 York Avenue Box 65, New York, NY 10065, USA., CCR-SF Bioinformatics Group, Advanced Biomedical and Computational Sciences, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA., Confocal Microscopy and Digital Imaging Facility, Experimental Immunology Branch, CCR, NCI NIH Bldg 10 Rm 4A05, Bethesda, MD 20892, USA., Division of Hematology/Oncology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA., Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.,

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. © 2024 Published by Elsevier Inc.

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