SWI/SNF Activity Is Required for the Repression of Deoxyribonucleotide Triphosphate Metabolic Enzymes via the Recruitment of mSin3B

Abstract

The SWI/SNF chromatin remodeling complex plays a critical role in the coordination of gene expression with physiological stimuli. The synthetic enzymes ribonucleotide reductase, dihydrofolate reductase, and thymidylate synthase are coordinately regulated to ensure appropriate deoxyribonucleotide triphosphate levels. Particularly, these enzymes are actively repressed as cells exit the cell cycle through the action of E2F transcription factors and the retinoblastoma tumor suppressor/p107/p130 family of pocket proteins. This process is found to be highly dependent on SWI/SNF activity as cells deficient in BRG-1 and Brm subunits fail to repress these genes with activation of pocket proteins, and this deficit in repression can be complemented, via the ectopic expression of BRG-1. The failure to repress transcription does not involve a blockade in the association of E2F or pocket proteins p107 and p130 with promoter elements. Rather, the deficit in repression is due to a failure to mediate histone deacetylation of ribonucleotide reductase, dihydrofolate reductase, and thymidylate synthase promoters in the absence of SWI/SNF activity. The basis for this is found to be a failure to recruit mSin3B and histone deacetylase proteins to promoters. Thus, the coordinate repression of deoxyribonucleotide triphosphate metabolic enzymes is dependent on the action of SWI/SNF in facilitating the assembly of repressor complexes at the promoter.SWI/SNF is a multisubunit complex that regulates transcription through its ability to remodel chromatin (1-4). This complex contains either BRG-1 or Brm as the central ATPase. Additionally, the complex is composed of accessory proteins termed BRG-1-associated factors (5). Together, these subunits form a 2-MDa complex that utilizes the energy from ATP hydrolysis to catalyze changes in chromatin structure. Given this central role for SWI/SNF in transcriptional control, the complex is associated with multiple biological processes including differentiation, hormonal signaling, and cell cycle control. The SWI/SNF complex is important for modulating transcriptional programs related to cell cycle control, and aberrations in SWI/SNF subunits are progressively associated with tumorigenesis (6, 7).Specifically, SNF5 is a tumor suppressor involved in rhabdoid tumors (8 -10), while sporadic loss of multiple other subunits is observed in a litany of tumor types (11). In general, the loss of these factors has been implicated in deregulation of target genes associated with cell cycle control, particularly those regulated by the RB/E2F signaling axis (12-14).The retinoblastoma tumor suppressor (RB) 2 was identified based on loss in the pediatric eye tumor of the same name (15-18). Subsequently, the gene product has been extensively analyzed and demonstrated to function as a transcriptional modulator. Specifically, RB and related pocket proteins p107/p130 bind to members of the E2F family of transcription factors and mediate transcriptional repression (19 -23). These effects on transcription are mediated by th...

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