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.
Highlights
The genomic DNA in eukaryotic cells nuclei is packaged together with histone proteins into a complex called chromatin, enabling the storage of a relatively large amount of DNA in a very compacted form
BRM deficiency or downregulation was found in various types of cancer, its function in cancer development and progression remains elusive
The mutation rate in SMARCA2 gene is quite rare compared to mutations in SMARCA4, suggesting a less important role of BRM ATPase containing switch/ sucrose non-fermenting (SWI/SNF) chromatin-remodelling complex (CRC) in carcinogenesis
Summary
Background The genomic DNA in eukaryotic cells nuclei is packaged together with histone proteins into a complex called chromatin, enabling the storage of a relatively large amount of DNA in a very compacted form. In CSS the duplication of SMARCA2 gene may lead to overexpression of BRM protein and as a consequence altered SWI/SNF stoichiometry caused by the pathological competition of BRM with BRG1 ATPase. It is important to note that the classes of human SWI/SNF CRCs containing BRG1 or BRM subunits may regulate different promoters and sometimes they even differentially regulate transcription of the same genes [19]. This could be based on the differences in transcription factor recruitment, subunit composition and the occurrence of differential modifications of SWI/SNF subunits [23].
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