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Different SWI/SNF complexes coordinately promote R-loop- and RAD52- dependent transcription-coupled homologous recombination

ABSTRACT: The SWI/SNF family of ATP-dependent chromatin remodeling complexes are implicated in multiple DNA damage response mechanisms and frequently mutated in cancer. The BAF and PBAF complexes are two major types of SWI/SNF complexes that are functionally distinguished by their exclusive subunits. Accumulating evidence suggests that double-strand breaks (DSBs) in transcriptionally active DNA are preferentially repaired by a dedicated homologous recombination pathway. We show that different BAF and PBAF subunits promote homologous recombination and are rapidly recruited to DSBs in a transcription-dependent manner. The PBAF complex promotes RNA polymerase II eviction near DNA damage to rapidly initiate transcriptional silencing, while the BAF complex helps to maintain this transcriptional silencing. Furthermore, ARID1A-containing BAF complexes promote RNaseH1 and RAD52 recruitment to facilitate R-loop resolution and DNA repair. Our results highlight how multiple SWI/SNF complexes perform different functions to enable DNA repair in the context of actively transcribed genes.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Jeroen Demmers

LAB HEAD: Jeroen Demmers

PROVIDER: PXD035140 | Pride | 2023-07-31

REPOSITORIES: Pride

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Structure of nucleosome-bound human PBAF complex

Project description:BAF and PBAF are mammalian SWI/SNF family chromatin remodeling complexes that possess multiple histone/DNA-binding subunits and create nucleosome-depleted/free regions for transcription activation. Despite previous structural studies and recent advance of SWI/SNF family complexes, it remains incompletely understood how PBAF-nucleosome complex is organized. Here we determined structure of 13-subunit human PBAF in complex with acetylated nucleosome in ADP-BeF3-bound state. Four PBAF-specific subunits work together with nine BAF/PBAF-shared subunits to generate PBAF-specific modular organization, distinct from that of BAF at various regions. PBAF-nucleosome structure reveals six histone-binding domains and four DNA-binding domains/modules, the majority of which directly bind histone/DNA. This multivalent nucleosome-binding pattern, not observed in previous studies, suggests that PBAF may integrate comprehensive chromatin information to target genomic loci for function. Our study reveals molecular organization of subunits and histone/DNA-binding domains/modules in PBAF-nucleosome complex and provides structural insights into PBAF-mediated nucleosome association complimentary to the recently reported PBAF-nucleosome structure.

2023-03-11 | PXD036708 | Pride

Brd7, a novel PBAF-specific SWI/SNF subunit, is required for gene activation and repression in embryonic stem cells

Project description:The composition of chromatin remodeling complexes dictates how these enzymes control transcriptional programs and cellular identity. Here, we investigate the composition of SWI/SNF complexes in embryonic stem cells (ESCs). In contrast to differentiated cells, ESCs have a biased incorporation of certain paralogous SWI/SNF subunits, with low levels of Brm, BAF170 and ARID1B. Upon differentiation, the expression of these subunits increases, resulting in a higher diversity of compositionally distinct SWI/SNF enzymes. We also identify Brd7 as a novel component of the PBAF complex in both ESCs and differentiated cells. Using shRNA-mediated depletion of Brg1, we show that SWI/SNF can function as both a repressor and an activator in pluripotent cells, regulating expression of developmental modifiers and signaling components such as Nodal, ADAMTS1, Bmi-1, CRABP1 and TRH. Knock-down studies of PBAF-specific Brd7 and of a signature subunit within the BAF complex, ARID1A, show that these two sub-complexes affect SWI/SNF target genes differentially, in some cases even antagonistically. This may be due to their different biochemical properties. Finally, we examine the role of SWI/SNF in regulating its target genes during differentiation. We find that SWI/SNF affects recruitment of components of the pre-initiation complex in a promoter-specific manner, to modulate transcription positively or negatively. Taken together, our results provide insight into the function of compositionally diverse SWI/SNF enzymes that underlie their inherent gene-specific mode of action. R1 ESCs were infected in duplicates with shRNA targeting Brg1 or GLUT4 (as a control). Knockdown of Brg1 mRNA affected Brg1 protein levels efficiently. RNA was isolated 67 hours post-infection and analyzed using microarrays.

2010-03-04 | E-GEOD-7791 | biostudies-arrayexpress

IL-10 transcription is negatively regulated by BAF180, a component of the SWI/SNF chromatin remodeling enzyme

Project description:Several versions of SWI/SNF complexes, BAF and PBAF, have been described based on unique subunit composition. We find that T cell development in the thymus and lymphoid periphery is largely normal in the absence of the PBAF-specific component BAF180. However, BAF180-deficient Th2 cells express high levels of the immunoregulatory cytokine IL-10. BAF180 binds directly to regulatory elements in the Il-10 locus but is replaced by BAF250 BAF complexes in the absence of BAF180, resulting in increased histone acetylation and CBP recruitment to the IL-10 locus. These results demonstrate that BAF180 is a repressor of IL-10 transcription in Th2 cells and suggest that the differential recruitment of different SWI/SNF subtypes can have direct consequences on chromatin structure and gene transcription.

2012-03-27 | GSE31676 | GEO

BRD9 defines a novel SWI/SNF sub-complex and constitutes a specific vulnerability in malignant rhabdoid tumors [RNA-seq 2]

Project description:Bromodomain-containing protein 9 (BRD9) was recently identified to be associated with the chromatin remodeling SWI/SNF(BAF) complex, yet its function within the complex has remained unclear. Here, using genome-scale CRISPR-Cas9 screens, we found that BRD9 constitutes a specific vulnerability in highly malignant pediatric rhabdoid tumors, which are driven by inactivating mutations of SMARCB1 subunit of SWI/SNF complexes. Surprisingly, we found that BRD9 does not belong to the previously identified BAF or PBAF complexes, but instead is found exclusively in a novel of SWI/SNF sub-complex. We show that BRD9-containing complexes lack SMARCB1, which had previously been considered a core subunit present in all SWI/SNF variants. We recently demonstrated that both SMARCB1-containing and ARID1A-containing SWI/SNF complexes preferentially function at enhancers, but here we show that BRD9-containing complexes are located at active promoters as well as enhancers. We show that loss of SMARCB1, as observed in rhabdoid tumors, results in increased BRD9 interaction with SWI/SNF core subunit SMARCC1, consistent with competition between SMARCB1 and BRD9 in the formation of SWI/SNF complexes. Underlying the dependency, we demonstrate that BRD9, via its DUF3512 domain, is essential for maintaining the integrity of its sub-complex, which predominates in the absence of SMARCB1. Taken together, our results reveal a BRD9-containing SWI/SNF subcomplex which is required for the survival of SMARCB1-mutant rhabdoid tumors.

2019-03-14 | GSE125775 | GEO

BRD9 defines a novel SWI/SNF sub-complex and constitutes a specific vulnerability in malignant rhabdoid tumors [ChIP-seq]

2019-03-14 | GSE120234 | GEO

BRD9 defines a novel SWI/SNF sub-complex and constitutes a specific vulnerability in malignant rhabdoid tumors [RNA-seq]

2019-03-14 | GSE120233 | GEO

Drosophila BAF complex crosslinking (

Project description:Mammalian SWI/SNF (mSWI/SNF) ATP-dependent chromatin remodeling complexes are large, multisubunit molecular machines that play vital roles in regulating genomic architecture and are frequently disrupted in human cancer and developmental disorders. To date, the organization and pathway of assembly of these chromatin regulators remain unknown, presenting a major barrier to structural and functional determination. Here we elucidate the architecture and assembly pathway of three different classes of mammalian SWI/SNF complexes: canonical BAF, PBAF, and a newly defined complex, ncBAF, and define the requirement of each subunit for complex formation and stability. Using affinity purification of endogenous complexes from mammalian and Drosophila cells coupled with cross linking-mass spectrometry, we uncover three distinct and evolutionarily conserved modules, their organization, and the temporal incorporation of these modules into each complete mSWI/SNF complex class.

2018-10-18 | PXD010123 | Pride

Human pBAF complex (HA-BRD7, PHF10-HA pulldown)

2018-10-18 | PXD010122 | Pride

Brd7, a novel PBAF-specific SWI/SNF subunit, is required for gene activation and repression in embryonic stem cells

2009-04-01 | GSE7791 | GEO

SWI/SNF-dependent genes are defined by their chromatin landscape [RNA-seq]

Project description:The SWI/SNF complex was the first chromatin remodeling machinery discovered. Although it has been extensively investigated, numerous aspects of its regulation and activity are still poorly understood, especially in higher eukaryotes. In mammals, there is not a single SWI/SNF complex (also called BRM or BRG1 associated factors, BAF, complex) but rather a polymorphic family of complexes, with three main subtypes called canonical BAF (cBAF), polybromo-associated BAF (PBAF), and non-canonical BAF (ncBAF), with relatively different specificities. The enzymatic motors of the complexes are two mutually exclusive ATPases of the SNF2 family called BRAHMA (BRM, also called SMARCA2) and BRAHMA RELATED GENE 1 (BRG1, also called SMARCA4). Recently, an specific inhibitor of BRM and BRG1 ATPase activity, called BRM014, has been developed. We have extensively investigated the effect of BRM014 on the transcriptome and the chromatin landscape of non-tumoral normal murine mammary (NMuMG) epithelial cells.

2024-03-08 | GSE226953 | GEO

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