Altered control of cellular proliferation in the absence of mammalian brahma (SNF2 alpha)

The mammalian SWI-SNF complex is an evolutionarily conserved, multi-subunit machine, involved in chromatin remodelling during transcriptional activati on. Within this complex, the BRM (SNF2 alpha) and BRG1 (SNF2 beta) proteins are mutually exclusive subunits that are believed to affect nucleosomal st ructures using the energy of ATP hydrolysis. In order to characterize possi ble differences in the function of BRM and BRG1, and to gain further insigh ts into the role of BRM-containing SWI-SNF complexes, the mouse BRM gene wa s inactivated by homologous recombination. BRM-/- mice develop normally, su ggesting that an observed up-regulation of the BRG1 protein can functionall y replace BRM in the SWI-SNF complexes of mutant cells. Nonetheless, adult mutant mice were similar to 15% heavier than control littermates. This may be caused by increased cell proliferation, as demonstrated by a higher mito tic index detected in mutant livers. This is supported further by the obser vation that mutant embryonic fibroblasts were significantly deficient in th eir ability to arrest in the G(0)/G(1) phase of the cell cycle in response to cell confluency or DNA damage. These studies suggest that BRM participat es in the regulation of cell proliferation in adult mice.