The Activity of p53 Is Differentially Regulated by Brm- and Brg1-containing SWI/SNF Chromatin Remodeling Complexes

Abstract

Brahma (Brm) and Brahma-related gene-1 (Brg1) ATPases share similarities in structure and function, but their presence in human SWI/SNF chromatin remodeling complexes is mutually exclusive. Although Brm and Brg1 can compensate for each other, it is possible that Brm and Brg1 have their unique properties to differentially regulate gene expression in vivo. To explore this, we examined the requirement of Brm and Brg1 for p53-dependent transcription, especially p53-mediated induction of p21 and MDM2, using cell lines in which Brm or Brg1 could be inducibly knocked down. We found that Brg1, but not Brm, is required for p21 induction in MCF7 cells. However, in Brg1-deficient H1299 cells, Brm is also required for p21 induction. Likewise, Brm is necessary for induction of p21 in MCF7 cells in which Brg1 is stably knocked down. In contrast, Brg1 has little, if any, effect on p53-mediated induction of MDM2 in cells that have Brm and vice versa. In addition, we demonstrated that the impaired induction of p21 upon Brg1 knockdown is at least in part due to decreased p53 binding to the p21 promoter. Taken together, we provided evidence that Brg1 is preferentially recruited by p53 for inducing a subset of target genes through chromatin remodeling. Thus, we hypothesize that the potential tumor suppressor function for Brg1 is mediated in part through the p53 pathway.The highly condensed chromatin packaged with genomic DNA forms a repressive structure that tends to restrict the access of transcription factors and co-factors to DNA, and relief from this repression by chromatin remodeling is critical for gene transcription (1-3). Generally, chromatin remodeling is achieved through two mechanisms: covalent modifications such as acetylation of histone tails and disruption or alteration of the local histone-DNA association by ATP-dependent chromatin remodeling complexes (3, 4). Currently, four distinct classes of chromatin remodeling complexes, SWI/SNF, ISWI, Mi-2, and Ino80, have been identified (5-7).All chromatin remodeling complexes contain a core ATPase that has a homology to the yeast SWI2/SNF2 (8). Human SWI/ SNF chromatin remodeling complexes contain either Brahma (Brm) 3 or Brahma-related gene 1 (Brg1) as an ATPase subunit (7). Brm and Brg1 are evolutionarily conserved with a considerable degree of amino acid sequence identity, and their functions appear to be partially redundant. It has been well established that Brg1 and Brm are involved in transcriptional activation as well as transcriptional repression for a subset of genes (9). For example, both Brm and Brg1 are required for activation of genes such as CD44 (10) and EPO (11) and interact with prohibitin (12) and TopBP (13) for transcriptional repression. Moreover, Brg1 can functionally replace Brm and vice versa (14). Nevertheless, the presence of Brm and Brg1 in an SWI/SNF chromatin remodeling complex is mutually exclusive, and functional differences between Brm and Brg1 have been implicated from in vitro and in vivo studies. First, knockout mice studies revealed that B...

DNA Topoisomerase III Alpha Regulates p53-Mediated Tumor Suppression

“…Nevertheless, our and other studies also suggest an existence of p53-independent mechanism(s) in tumor suppression. RNAi technology has allowed the search for novel tumor suppressors using a genetically defined tumorigenic system (43,44), leading to the discovery of chromatin-modifying factors, including BRD7, TIP60, and HDAC4 (5,9,43). Similar to our findings on hTOP3a, these enzymes either serve as cofactors of p53 on tumor suppression or are required for its optimal transcriptional activity.…”

“…Through the interactions with p53, chromatin factors modulate p53 expression and p53-mediated tumor suppression (5,8,9). Here, we have identified the topology-resolving hTOP3a protein as a candidate anticancer block in p53-mediated tumor suppression.…”

“…In addition to genetic alterations, other p53 inactivation mechanisms via BRD7 (bromodomain-containing 7) dysfunction or elevated microRNA expression have been reported in cancers (5)(6)(7). Chromatin modifying and remodeling complexes have also shown to regulate p53-dependent p21 expression (8,9). Notably, recent reports on cancer genomic analyses revealed the potential contribution of chromatin factors to tumorigenesis (10).…”

Polybromo-associated BRG1-associated factor components BRD7 and BAF180 are critical regulators of p53 required for induction of replicative senescence

“…A previous study showed that the specifying component exclusive to the PBAF complex, BAF180 (polybromo-1), physically binds the p21 promoter (10). This observation was also made regarding BRG1, which functions interchangeably with structurally related BRM1 as one of the two SWI/SNF ATPase subunits in BAF complexes, although it is the only ATPase subunit used by the PBAF complex (11,12). Here, we show that BRD7 is a critical mediator of the ability of p53 to transduce the replicative and oncogene-induced senescence signal to p21 to initiate the senescence program of differentiation.…”

Essential role of BRG, the ATPase subunit of BAF chromatin remodeling complexes, in leukemia maintenance

“…Distinct functions for BRM-and BRG-based complexes have been observed in smooth muscle development, 15 osteoblast differentiation, 16 as well as cellular proliferation. 14,[17][18][19][20][21][22] BRM depletion is essential for neoplastic transformation of mouse fibroblasts by various oncogenes and its overexpression is sufficient to revert the RasV12 transformed phenotype. 17 In contrast to BRM, BRG is essential for oncogenic transformation of mouse fibroblasts and tumor formation in BAF47 null mice.…”