Browse
Submit Data
Databases
API
Help

Dataset Information

28 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

BRG1 Promotes chromatin remodeling around DNA damage sites.

ABSTRACT: Chromatin remodeling complexes play important roles in various DNA metabolism processes, including DNA damage repair. BRG1 is the core subunit of the SWI/SNF complex, which plays critical roles in cell cycle regulation, cell development, cell differentiation, and tumorigenesis. In the present study, we report that BRG1 depletion increased the percentage of apoptotic cells in etoposide-treated cells. Moreover, western blotting and immunofluorescence data showed that BRG1 depletion decreased H2AX phosphorylation and caused defective phosphorylated histone H2AX (?H2AX) clearance. Furthermore, we found that in both SW13 and U2OS cells, BRG1 expression could increase the sensitivity of genomic DNA to micrococcal nuclease (MNase) and facilitate chromatin relaxation around DNA damage sites. Thus, the results provide evidence that BRG1 plays an important role in early DNA damage repair by remodeling the chromatin structure near DNA damage sites.

SUBMITTER: Qi W

PROVIDER: S-EPMC6282460 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

BRG1 Promotes chromatin remodeling around DNA damage sites.

Qi Wenjing W Chen Hongyu H Lu Chengwen C Bu Qingpan Q Wang Xiaoguang X Han Liping L

Animal cells and systems 20181001 6

Chromatin remodeling complexes play important roles in various DNA metabolism processes, including DNA damage repair. BRG1 is the core subunit of the SWI/SNF complex, which plays critical roles in cell cycle regulation, cell development, cell differentiation, and tumorigenesis. In the present study, we report that BRG1 depletion increased the percentage of apoptotic cells in etoposide-treated cells. Moreover, western blotting and immunofluorescence data showed that BRG1 depletion decreased H2AX ...[more]

PMID: 30533258

Similar Datasets

A PARP1-BRG1-SIRT1 axis promotes HR repair by reducing nucleosome density at DNA damage sites.

Project description:Creating access to DNA double-strand break (DSB) sites in the chromatin context is an essential step during the repair process, but much remains to be determined about its regulatory mechanisms. Here, using a novel reporter cassette for simultaneous detection of homologous recombination (HR) and nonhomologous end joining (NHEJ) at the same chromosomal site, we report that the efficiency of HR but not NHEJ negatively correlates with nucleosome density. We demonstrate that PARP1 is required for HR by modulating nucleosome density at damage sites. Mechanistic studies indicate that the ATPase domain of BRG1 and the ZnF domain of SIRT1 interact with poly-ADP ribose (PAR) in response to DNA damage, and are responsible for bringing the two factors to broken DNA ends. At DNA damage sites, BRG1 and SIRT1 physically interact, whereupon SIRT1 deacetylates BRG1 at lysine residues 1029 and 1033, stimulating its ATPase activity to remodel chromatin and promote HR.

| S-EPMC7145522 | biostudies-literature

Rsf-1, a chromatin remodeling protein, induces DNA damage and promotes genomic instability.

Project description:Rsf-1 (HBXAP) has been reported as an amplified gene in human cancer, including the highly aggressive ovarian serous carcinoma. Rsf-1 protein interacts with SNF2H to form an ISWI chromatin remodeling complex, RSF. In this study, we investigated the functional role of Rsf-1 by observing phenotypes after expressing it in nontransformed cells. Acute expression of Rsf-1 resulted in DNA damage as evidenced by DNA strand breaks, nuclear ?H2AX foci, and activation of the ATM-CHK2-p53-p21 pathway, leading to growth arrest and apoptosis. Deletion mutation and gene knockdown assays revealed that formation of a functional RSF complex with SNF2H was required for Rsf-1 to trigger DNA damage response (DDR). Gene knock-out of TP53 alleles, TP53 mutation, or treatment with an ATM inhibitor abolished up-regulation of p53 and p21 and prevented Rsf-1-induced growth arrest. Chronic induction of Rsf-1 expression resulted in chromosomal aberration and clonal selection for cells with c-myc amplification and CDKN2A/B deletion. Co-culture assays indicated Rsf-1-induced DDR as a selecting barrier that favored outgrowth of cell clones with a TP53 mutation. The above findings suggest that increased Rsf-1 expression and thus excessive RSF activity, which occurs in tumors harboring Rsf-1 amplification, can induce chromosomal instability likely through DDR.

| S-EPMC2992260 | biostudies-other

KDM2B promotes IL-6 production and inflammatory responses through Brg1-mediated chromatin remodeling.

Project description:IL-6 plays important and pleiotropic roles in infection and inflammatory diseases, and its production needs to be tightly regulated. However, the epigenetic mechanism underlying Il6 gene transcription remains to be fully elucidated. Here, we report that lysine-specific demethylase 2b (KDM2B), which demethylates H3K4me3 and H3K36me2, is required in macrophages and dendritic cells for the induction of IL-6 but not TNF-α, IL-1, and IFN-β. Compared to wild-type mice, KDM2B-deficient mice were more resistant to endotoxin shock and colitis, with a less severe inflammatory pathogenesis phenotype and decreased IL-6 production in sera. KDM2B selectively bound the Il6 promoter but did not alter histone demethylation; instead, KDM2B interacted with Brahma-related gene 1 (Brg1), the core ATPase subunit of SWI/SNF chromatin remodeling complexes, to facilitate chromatin accessibility of the Il6 promoter. Furthermore, KDM2B directly recruited RNA Polymerase II to further initiate and promote Il6 transcription. Thus, our finding identifies a novel nonclassical function of KDM2B in gene-specific transcription initiation and enhancement of Il6 independent of its demethylase activity and adds new insight into the specific epigenetic modification mechanism of inflammatory immune responses.

| S-EPMC7395766 | biostudies-literature

The chromatin-remodeling enzyme BRG1 promotes colon cancer progression via positive regulation of WNT3A.

Project description:In this study, we aimed to elucidate the clinical significance and underlying mechanisms of BRG1 in colon cancer. In the clinical analysis, overexpression of BRG1 correlates with colon cancer progression in two cohorts (n = 191 and n = 75). Kaplan-Meier survival analysis revealed that BRG1 is a prognosis predictor for overall survival (P < 0.001) and disease-free survival (P = 0.001). Knocking down BRG1 expression significantly suppressed the proliferation and invasion in colon cancer cells. The expression pattern of WNT3A is consistent with BRG1 in colon cancer tissues and WNT3A expression was inhibited in BRG1 knockdown cells. In addition, restoring WNT3A expression rescues the inhibition of cell proliferation and invasion induced by BRG1. In this study, we demonstrate that BRG1 may contribute to colon cancer progression through upregulating WNT3A expression.

| S-EPMC5349896 | biostudies-literature

ISWI chromatin remodeling complexes in the DNA damage response.

Project description:Regulation of chromatin structure is an essential component of the DNA damage response (DDR), which effectively preserves the integrity of DNA by a network of multiple DNA repair and associated signaling pathways. Within the DDR, chromatin is modified and remodeled to facilitate efficient DNA access, to control the activity of repair proteins and to mediate signaling. The mammalian ISWI family has recently emerged as one of the major ATP-dependent chromatin remodeling complex families that function in the DDR, as it is implicated in at least 3 major DNA repair pathways: homologous recombination, non-homologous end-joining and nucleotide excision repair. In this review, we discuss the various manners through which different ISWI complexes regulate DNA repair and how they are targeted to chromatin containing damaged DNA.

| S-EPMC4615051 | biostudies-other

The chromatin-remodeling subunit Baf200 promotes homology-directed DNA repair and regulates distinct chromatin-remodeling complexes.

Project description:The efficiency and type of pathway chosen to repair DNA double-strand breaks (DSBs) are critically influenced by the nucleosome packaging and the chromatin architecture surrounding the DSBs. The Swi/Snf (PBAF and BAF) chromatin-remodeling complexes contribute to DNA damage-induced nucleosome remodeling, but the mechanism by which it contributes to this function is poorly understood. Herein, we report how the Baf200 (Arid2) PBAF-defining subunit regulates DSB repair. We used cytological and biochemical approaches to show that Baf200 plays an important function by facilitating homologous recombination-dependent processes, such as recruitment of Rad51 (a key component of homologous recombination) to DSBs, homology-directed repair, and cell survival after DNA damage. Furthermore, we observed that Baf200 and Rad51 are present in the same complex and that this interaction is mediated by C-terminal sequences in both proteins. It has been recognized previously that the interplay between distinct forms of Swi/Snf has profound functional consequences, but we understand little about the composition of complexes formed by PBAF protein subunits. Our biochemical analyses reveal that Baf200 forms at least two distinct complexes. One is a canonical form of PBAF including the Swi/Snf-associated Brg1 catalytic subunit, and the other contains Baf180 but not Brg1. This distinction of PBAF complexes based on their unique composition provides the foundation for future studies on the specific contributions of the PBAF forms to the regulation of DNA repair.

| S-EPMC5437250 | biostudies-literature

The BRG1 chromatin remodeling enzyme links cancer cell metabolism and proliferation.

Project description:Cancer cells reprogram cellular metabolism to meet the demands of growth. Identification of the regulatory machinery that regulates cancer-specific metabolic changes may open new avenues for anti-cancer therapeutics. The epigenetic regulator BRG1 is a catalytic ATPase for some mammalian SWI/SNF chromatin remodeling enzymes. BRG1 is a well-characterized tumor suppressor in some human cancers, but is frequently overexpressed without mutation in other cancers, including breast cancer. Here we demonstrate that BRG1 upregulates de novo lipogenesis and that this is crucial for cancer cell proliferation. Knockdown of BRG1 attenuates lipid synthesis by impairing the transcription of enzymes catalyzing fatty acid and lipid synthesis. Remarkably, exogenous addition of palmitate, the key intermediate in fatty acid synthesis, rescued the cancer cell proliferation defect caused by BRG1 knockdown. Our work suggests that targeting BRG1 to reduce lipid metabolism and, thereby, to reduce proliferation, has promise for epigenetic therapy in triple negative breast cancer.

| S-EPMC5122388 | biostudies-literature

Transcriptional repressor ZBTB1 promotes chromatin remodeling and translesion DNA synthesis.

Project description:Timely DNA replication across damaged DNA is critical for maintaining genomic integrity. Translesion DNA synthesis (TLS) allows bypass of DNA lesions using error-prone TLS polymerases. The E3 ligase RAD18 is necessary for proliferating cell nuclear antigen (PCNA) monoubiquitination and TLS polymerase recruitment; however, the regulatory steps upstream of RAD18 activation are less understood. Here, we show that the UBZ4 domain-containing transcriptional repressor ZBTB1 is a critical upstream regulator of TLS. The UBZ4 motif is required for PCNA monoubiquitination and survival after UV damage. ZBTB1 associates with KAP-1, a transcriptional repressor whose phosphorylation relaxes chromatin after DNA damage. ZBTB1 depletion impairs formation of phospho-KAP-1 at UV damage sites and reduces RAD18 recruitment. Furthermore, phosphorylation of KAP-1 is necessary for efficient PCNA modification. We propose that ZBTB1 is required for localizing phospho-KAP-1 to chromatin and enhancing RAD18 accessibility. Collectively, our study implicates a ubiquitin-binding protein in orchestrating chromatin remodeling during DNA repair.

| S-EPMC3989074 | biostudies-literature

Rad51 accumulation at sites of DNA damage and in postreplicative chromatin.

Project description:Rad51, a eukaryotic RecA homologue, plays a central role in homologous recombinational repair of DNA double-strand breaks (DSBs) in yeast and is conserved from yeast to human. Rad51 shows punctuate nuclear localization in human cells, called Rad51 foci, typically during the S phase (Tashiro, S., N. Kotomura, A. Shinohara, K. Tanaka, K. Ueda, and N. Kamada. 1996. Oncogene. 12:2165-2170). However, the topological relationships that exist in human S phase nuclei between Rad51 foci and damaged chromatin have not been studied thus far. Here, we report on ultraviolet microirradiation experiments of small nuclear areas and on whole cell ultraviolet C (UVC) irradiation experiments performed with a human fibroblast cell line. Before UV irradiation, nuclear DNA was sensitized by the incorporation of halogenated thymidine analogues. These experiments demonstrate the redistribution of Rad51 to the selectively damaged, labeled chromatin. Rad51 recruitment takes place from Rad51 foci scattered throughout the nucleus of nonirradiated cells in S phase. We also demonstrate the preferential association of Rad51 foci with postreplicative chromatin in contrast to replicating chromatin using a double labeling procedure with halogenated thymidine analogues. This finding supports a role of Rad51 in recombinational repair processes of DNA damage present in postreplicative chromatin.

| S-EPMC2180223 | biostudies-literature

Biased chromatin signatures around polyadenylation sites and exons.

Project description:Core RNA-processing reactions in eukaryotic cells occur cotranscriptionally in a chromatin context, but the relationship between chromatin structure and pre-mRNA processing is poorly understood. We observed strong nucleosome depletion around human polyadenylation sites (PAS) and nucleosome enrichment just downstream of PAS. In genes with multiple alternative PAS, higher downstream nucleosome affinity was associated with higher PAS usage, independently of known PAS motifs that function at the RNA level. Conversely, exons were associated with distinct peaks in nucleosome density. Exons flanked by long introns or weak splice sites exhibited stronger nucleosome enrichment, and incorporation of nucleosome density data improved splicing simulation accuracy. Certain histone modifications, including H3K36me3 and H3K27me2, were specifically enriched on exons, suggesting active marking of exon locations at the chromatin level. Together, these findings provide evidence for extensive functional connections between chromatin structure and RNA processing.

| S-EPMC2786773 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data