A Chromatin Remodeling Complex Regulates Topoisomerase IIα Function

Components of the mammalian SWI/SNF (or BAF) chromatin remodeling complex, particularly the core ATPase BRG1 (also known as SMARCA4) and BAF250A (also known as ARID1A), are frequently mutated in such human tumors as medulloblastoma and Burkitt lymphoma. However, the mechanisms by which these proteins suppress tumorigenesis remain unknown. Dykhuizen and colleagues found that deletion of Brg1 in mouse embryonic stem cells induced the formation of anaphase bridges, indicative of sister chromatids linked by catenated DNA strands that are normally resolved by topoisomerase IIα (TOP2A) during mitosis. This phenotype was associated with G₂–M cell-cycle arrest via the decatenation checkpoint and resembled the mitotic defect triggered by TOP2A inhibition or depletion, suggesting that BRG1 is required for proper regulation of TOP2A function. In support of this idea, increased anaphase bridges were detected in a small panel of primary human BRG1-mutant medulloblastoma samples, and expression of oncogenic mutant BRG1 proteins enhanced the incidence of mitotic defects, resulting in a greater number of polyploid cells. These BRG1 mutant proteins exhibited impaired ATPase activity and disrupted the interaction of TOP2A with chromatin at BRG1-binding, DNase I-hypersensitive sites across the genome, indicating that the enzymatic activity of BRG1 is required for TOP2A accessibility to substrate DNA. In addition, BAF complex–mediated regulation of TOP2A function was dependent on the interaction of TOP2A with BRG1 through direct association with the BAF250A subunit, as BAF250A depletion phenocopied the effect of TOP2A inhibition. These findings identify a previously uncharacterized role for the BAF complex in the regulation of TOP2A function and DNA decatenation in mitosis. In addition, these results may explain the high frequency of BRG1 and BAF250A mutations in human cancer and suggest that BAF complex activity may limit chromosome instability and contribute to tumor suppression.

Dykhuizen EC, Hargreaves DC, Miller EL, Cui K, Korshunov A, Kool M, et al. BAF complexes facilitate decatenation of DNA by topoisomerase IIα. Nature 2013 May 22 [Epub ahead of print].