SWI/SNF activity is required for the repression of deoxyribonucleotide triphosphate metabolic enzymes via the recruitment of mSin3B.
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.
Gunawardena
Ranjaka W
RW
Department of Cell and Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0521, USA.
Fox
Sejal R
SR
Siddiqui
Hasan
H
Knudsen
Erik S
ES
D002453:Cell Cycle / Q000502:physiology*; D002460:Cell Line; D042002:Chromatin Assembly and Disassembly / Q000502:physiology*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D004265:DNA Helicases / Q000172:deficiency / Q000378:metabolism; D003854:Deoxyribonucleotides / Q000235:genetics / Q000378:metabolism*; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009687:Nuclear Proteins / Q000172:deficiency / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000502:physiology; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D050720:Retinoblastoma-Like Protein p107 / Q000235:genetics / Q000378:metabolism; D050717:Retinoblastoma-Like Protein p130 / Q000235:genetics / Q000378:metabolism; D012264:Ribonucleotide Reductases / Q000235:genetics / Q000378:metabolism; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D013940:Thymidylate Synthase / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology*
D002868:Chromosomal Proteins, Non-Histone; D003854:Deoxyribonucleotides; D050684:E2F Transcription Factors; D009687:Nuclear Proteins; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130; C445179:SWI-SNF-B chromatin-remodeling complex; D014157:Transcription Factors; D012264:Ribonucleotide Reductases; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase; D006655:Histone Deacetylases; C084108:SMARCA4 protein, human; D004265:DNA Helicases