Abstract
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.
Highlights
It has been estimated that the genome within each individual human cell is subjected to tens of thousands of DNA lesions per day[1,2]
While endogenous DNA damage contributes to tumorigenesis, identifying how this occurs through mechanistic studies has been challenging
A recent genome-wide sequencing study reported that endogenous DNA damage is the major source of genome instability and mutational signatures in specific cancers[8]
Summary
It has been estimated that the genome within each individual human cell is subjected to tens of thousands of DNA lesions per day[1,2]. Bromodomains (BRDs) are acetyl-lysine binding motifs that are found in 42 proteins in mammalian cells[13] and include ATPdependent chromatin remodelers, histone acetyltransferase (HAT)-containing complexes, and transcriptional regulators. We describe how BRD proteins regulate replication processes to protect human cells from endogenous DNA damage and genome instability.
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