Bromodomain proteins: protectors against endogenous DNA damage and facilitators of genome integrity

Endogenous DNA damage is a major contributor to mutations, which are drivers of cancer development. Bromodomain (BRD) proteins are well-established participants in chromatin-based DNA damage response (DDR) pathways, which maintain genome integrity from cell-intrinsic and extrinsic DNA-damaging sources. BRD proteins are most well-studied as regulators of transcription, but emerging evidence has revealed their importance in other DNA-templated processes, including DNA repair and replication. How BRD proteins mechanistically protect cells from endogenous DNA damage through their participation in these pathways remains an active area of investigation. Here, we review several recent studies establishing BRD proteins as key influencers of endogenous DNA damage, including DNA–RNA hybrid (R-loops) formation during transcription and participation in replication stress responses. As endogenous DNA damage is known to contribute to several human diseases, including neurodegeneration, immunodeficiencies, cancer, and aging, the ability of BRD proteins to suppress DNA damage and mutations is likely to provide new insights into the involvement of BRD proteins in these diseases. Although many studies have focused on BRD proteins in transcription, evidence indicates that BRD proteins have emergent functions in DNA repair and genome stability and are participants in the etiology and treatment of diseases involving endogenous DNA damage. Bromodomain (BRD) proteins, known to regulate gene expression, switching particular genes on and off, also play key roles in repairing DNA damage, and studying them may help identify treatments for various diseases, including cancer. DNA damage can occur during normal cellular metabolism, for example, during copying DNA and gene expression. DNA damage is implicated in tumor formation as well as in neurodegeneration, immunodeficiency, and aging. Seo Yun Lee and colleagues at The University of Texas at Austin, USA, have reviewed new results showing how BRD proteins function in repairing DNA damage. They report that when DNA is damaged during copying in BRD-deficient cells, tumors can result. They also report that defects in BRD proteins are often present in cancers. Studying how BRD proteins function in both healthy and diseased cells could help to identify new therapies.