Polybromo-1 bromodomain 5 (PBRM1 BD5)

Polybromo-1 (PBRM1), also known as BAF180, is a critical subunit of the PBAF (Polybromo-associated BAF) chromatin remodeling complex, which plays a vital role in regulating gene expression by altering chromatin structure (UniProt Q86U86). PBRM1 contains six tandem bromodomains (BD1-BD6) that function as readers of acetylated lysine residues on histone tails, with Bromodomain 5 (BD5) showing high affinity for acetylated histone H3, specifically H3K14ac (PubMed: 24633121). Mutations in PBRM1 are highly prevalent in clear cell renal cell carcinoma (ccRCC), where it acts as a major tumor suppressor, being the second most frequently mutated gene after VHL (Nature: 10.1038/nature12425). Despite its role as a tumor suppressor, the bromodomains of PBRM1 are significant therapeutic targets for chemical probe development and potential drug discovery to modulate PBAF activity in various cancers and to understand the biology of SWI/SNF-deficient cells. Small molecule inhibitors like PFI-3 and GSK2801 have been developed to selectively target these domains, providing tools to study the complex's role in DNA repair and transcriptional control (PubMed: 26912837). Understanding the specific contributions of BD5 is essential for developing precise epigenetic therapies that can exploit the vulnerabilities of tumors with altered chromatin remodeling pathways. Furthermore, PBRM1 status has emerged as a potential biomarker for predicting response to immune checkpoint inhibitors in certain oncology settings (PubMed: 29301961).

Other names

BAF180PB1Polybromo-1BRG1-associated factor 180

Competitive inhibition of acetylated lysine binding sites within the bromodomain, preventing the recruitment of the PBAF complex to specific genomic loci.