The role of SWI/SNF chromatin remodelling complex ATPase subunit - BRM in TNBC

Abstract BRM (BRAHMA) is a core, SWI2/SNF2-type ATPase subunit of SWI/SNF chromatin-remodelling complex (CRC) involved in various important regulatory processes including development. Mutations in SMARCA2, a BRM-encoding gene as well as overexpression or epigenetic silencing were found in various human diseases including cancer. Missense mutations in SMARCA2 gene were recently connected with occurrence of Nicolaides–Baraitser genetics syndrome. By contrast, SMARCA2 duplication rather than mutations is characteristic for Coffin–Siris syndrome. It is believed that BRM usually acts as a tumour suppressor or a tumour susceptibility gene. However, other studies provided evidence that BRM function may differ depending on the cancer type and the disease stage, where BRM may play a role in the disease progression. The existence of alternative splicing forms of SMARCA2 gene, leading to appearance of truncated functional, loss of function or gain-of-function forms of BRM protein suggest a far more complicated mode of BRM-containing SWI/SNF CRCs actions. Therefore, the summary of recent knowledge regarding BRM alteration in various types of cancer and highlighting of differences and commonalities between BRM and BRG1, another SWI2/SNF2 type ATPase, will lead to better understanding of SWI/SNF CRCs function in cancer development/progression. BRM has been recently proposed as an attractive target for various anticancer therapies including the use of small molecule inhibitors, synthetic lethality induction or proteolysis-targeting chimera (PROTAC). However, such attempts have some limitations and may lead to severe side effects given the homology of BRM ATPase domain to other ATPases, as well as due to the tissue-specific appearance of BRM- and BRG1-containing SWI/SNF CRC classes. Thus, a better insight into BRM-containing SWI/SNF CRCs function in human tissues and cancers is clearly required to provide a solid basis for establishment of new safe anticancer therapies.

Download Full-text

The role of the SWI/SNF chromatin remodelling complex in the response to DNA double strand breaks

DNA Repair ◽

10.1016/j.dnarep.2020.102919 ◽

2020 ◽

Vol 93 ◽

pp. 102919

Author(s):

Alison Harrod ◽

Karen A. Lane ◽

Jessica A. Downs

Keyword(s):

Chromatin Remodelling ◽

Double Strand Breaks ◽

Dna Double Strand Breaks ◽

Chromatin Remodelling Complex ◽

Strand Breaks

Download Full-text

A novel SNF2 ATPase complex in Trypanosoma brucei with a role in H2A.Z-mediated chromatin remodelling

10.1101/2021.04.06.438560 ◽

2021 ◽

Author(s):

Tim Vellmer ◽

Laura Hartleb ◽

Albert Fradera Sola ◽

Susanne Kramer ◽

Elisabeth Meyer-Natus ◽

...

Keyword(s):

Transcriptional Regulation ◽

Trypanosoma Brucei ◽

Chromatin Condensation ◽

Chromatin Remodelling ◽

Model Organisms ◽

Mrna Levels ◽

Histone H2a ◽

Atpase Subunit ◽

Chromatin Remodelling Complex ◽

Pol Ii

A cascade of histone acetylation events with subsequent incorporation of a histone H2A variant plays an essential part in transcription regulation in various model organisms. A key player in this cascade is the chromatin remodelling complex SWR1, which replaces the canonical histone H2A with its variant H2A.Z. Transcriptional regulation of polycistronic transcription units in the unicellular parasite Trypanosoma brucei has been shown to be highly dependent on acetylation of H2A.Z, which is mediated by the histone-acetyltransferase HAT2. The chromatin remodelling complex which mediates H2A.Z incorporation is not known and an SWR1 orthologue in trypanosomes has not yet been reported. In this study, we identified and characterised an SWR1-like remodeller complex in T. brucei that is responsible for Pol II-dependent transcriptional regulation. Bioinformatic analysis of potential SNF2 DEAD/Box helicases, the key component of SWR1 complexes, identified a 1211 amino acids-long protein that exhibits key structural characteristics of the SWR1 subfamily. Systematic protein-protein interaction analysis revealed the existence of a novel complex exhibiting key features of an SWR1-like chromatin remodeller. RNAi-mediated depletion of the ATPase subunit of this complex resulted in a significant reduction of H2A.Z incorporation at transcription start sites and a subsequent decrease of steady-state mRNA levels. Furthermore, depletion of SWR1 and RNA-polymerase II (Pol II) caused massive chromatin condensation. The potential function of several proteins associated with the SWR1-like complex and with HAT2, the key factor of H2A.Z incorporation, is discussed.

Download Full-text

Interaction of RSC chromatin remodelling complex with nucleosomes is modulated by H3 K14 acetylation and H2B SUMOylation in vivo

10.1101/2020.03.02.972562 ◽

2020 ◽

Author(s):

Neha Jain ◽

Davide Tamborrini ◽

Brian Evans ◽

Shereen Chaudhry ◽

Bryan J. Wilkins ◽

...

Keyword(s):

Histone Variants ◽

Chromatin Remodelling ◽

List Type ◽

Atpase Subunit ◽

Chromatin Remodelling Complex ◽

Key Points ◽

Target Sites ◽

Nucleosome Binding

AbstractChromatin remodelling complexes are multi-subunit nucleosome translocases that reorganize chromatin in the context of DNA replication, repair and transcription. A key question is how these complexes find their target sites on chromatin. Here, we use genetically encoded photo-crosslinker amino acids to map the footprint of Sth1, the catalytic subunit of the RSC (remodels the structure of chromatin) complex, on the nucleosome in living yeast. We find that the interaction of the Sth1 bromodomain with the H3 tail depends on K14 acetylation by Gcn5. This modification does not recruit RSC to chromatin but mediates its interaction with neighbouring nucleosomes. We observe a preference of RSC for H2B SUMOylated nucleosomes in vivo and show that this modification moderately enhances RSC binding to nucleosomes in vitro. Furthermore, RSC is not ejected from chromatin in mitosis, but its mode of nucleosome binding differs between interphase and mitosis. In sum, our in vivo analyses show that RSC recruitment to specific chromatin targets involves multiple histone modifications most likely in combination with other components such as histone variants and transcription factors.Key PointsIn vivo photo-crosslinking reveals the footprint of the ATPase subunit of RSC on the nucleosome.RSC binds to H3 K14ac nucleosomes via the C-terminal bromodomain of its ATPase-subunit Sth1.RSC preferentially localizes to H2B-SUMOylated nucleosomes.

Download Full-text

Tomato CRABS CLAW paralogues interact with chromatin remodelling factors to mediate carpel development and floral determinacy

10.1101/2021.08.19.456989 ◽

2021 ◽

Author(s):

Laura Castañeda ◽

Estela Gimenez ◽

Benito Pineda ◽

Begoña García-Sogo ◽

Ana Ortíz ◽

...

Keyword(s):

Crop Production ◽

Tomato Fruit ◽

Cell Activity ◽

Chromatin Remodelling ◽

Incomplete Penetrance ◽

Chromatin Remodelling Complex ◽

Stem Cell Activity ◽

Positive Regulators ◽

Carpel Development

CRABS CLAW (CRC) orthologues play a crucial role in floral meristem (FM) determinacy and gynoecium formation across angiosperms, key developmental processes for ensuring successful plant reproduction and crop production. Here, we revealed that the incomplete penetrance and variable expressivity of the carpel-inside-carpel phenotype observed in flowers of the tomato fruit iterative growth (fig) mutant is due to a lack of function of a homologue of the CRC gene, Solanum lycopersicum CRCa (SlCRCa). Likewise, a comprehensive functional analysis of SlCRCa and SlCRCb paralogues, including Arabidopsis complementation experiments, allowed us to propose that they operate as positive regulators of FM determinacy by acting in a compensatory and partially redundant manner to safeguard the proper formation of flowers and fruits. Furthermore, we provide the first evidence for the role of putative CRC orthologues as members of the chromatin remodelling complex that terminates floral stem cell activity by repressing WUSCHEL expression.

Download Full-text