The Role of BRG1 in Antioxidant and Redox Signaling

Abstract

Redox homeostasis is regulated by critical molecules that modulate antioxidant and redox signaling (ARS) within the cell. Imbalances among these molecules can lead to oxidative stress and damage to cell functions, causing a variety of diseases. Brahma-related gene 1 (BRG1), also known as SMARCA4, is the central ATPase catalytic subunit of the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex, which plays a core role in DNA replication, repair, recombination, and transcriptional regulation. Numerous recent studies show that BRG1 is involved in the regulation of various cellular processes associated with ARS. BRG1, as a major factor in chromatin remodeling, is essential for the repair of oxidative stress-induced DNA damage and the activation of antioxidant genes under oxidative stress. Consequently, a comprehensive understanding of the roles of BRG1 in redox homeostasis is crucial to understand the normal functioning as well as pathological mechanisms. In this review, we summarized and discussed the role of BRG1 in the regulation of ARS.

Figure 1

The figure illustrates interaction of BRG1 with Nrf2 that regulates the expression of several antioxidant genes. Under oxidative stress, the Keap1-CUL3 ubiquitination system is disrupted, resulting in the dissociation of Nrf2 and its translocation into the nucleus where it binds ARE, thereby promoting the expression of antioxidant genes. In response to oxidative stress, BRG1 also has a protective effect on mitochondrial function and regulates the UPR and ER stress by maintaining the basal level of Ire1 activity. ARE: antioxidant reaction element; ER: endoplasmic reticulum; CUL3: cullin 3; Keap1: Kelch-like ECH-associated protein-1; Nrf2: nuclear factor E2-related factor 2; UPR: unfolded protein response.

Figure 2

Pathways that are closely related to ROS levels implicated in BRG1 function in oxidative homeostasis. The summary diagram is simplified (see text for details).

Figure 3

The figure shows the transcriptional activation of BRG1 on a variety of ARS-related genes, including NOX (1,2,4), eNOS, CAV1, and autophagy-related genes. Interestingly, BRG1 not only restores the expression of eNOS to resist oxidative stress but also aggravates oxidative stress by activating CAV1 to limit eNOS activity and NO bioavailability. CAV1: caveolin-1; eNOS: endothelial nitric oxide synthase; NOX: NADPH oxidase complex.

Figure 4

Molecular associations of BRG1 with ARS-related targets. Schematic representation shows a wide variety of ARS-related targets regulated with BRG1. Ace: angiotensin-converting enzymes; CAMs: cell adhesion molecules; CAV1: caveolin-1; CCNB1: cyclin B1; C/EBPβ: CCAAT-enhancer-binding protein; CRP: C-reactive protein; ET-1: endothelin-1; EPO: erythropoietin; FoxM1: forkhead box M1; HSF1: heat shock factor 1; LGALS3: Galectin-3; LTBP2: latent TGF-β-binding protein 2; MCP-1: monocyte chemoattractant protein 1; MITF: microphthalmia-associated transcription factor; MKL1: megakaryocytic leukemia 1; MOF: males absent on the first; MTs: metallothioneins; PPARγ: peroxisome proliferators-activated receptor γ; RRAD: Ras-related associated with diabetes; SHH: Sonic hedgehog; TGF-β1: transforming growth factor beta 1.