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PMID:21102443

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Citation

Di, LJ, Fernandez, AG, De Siervi, A, Longo, DL and Gardner, K (2010) Transcriptional regulation of BRCA1 expression by a metabolic switch. Nat. Struct. Mol. Biol. 17:1406-13

Abstract

Though the linkages between germline mutations of BRCA1 and hereditary breast cancer are well known, recent evidence suggests that altered BRCA1 transcription may also contribute to sporadic forms of breast cancer. Here we show that BRCA1 expression is controlled by a dynamic equilibrium between transcriptional coactivators and co-repressors that govern histone acetylation and DNA accessibility at the BRCA1 promoter. Eviction of the transcriptional co-repressor and metabolic sensor, C terminal-binding protein (CtBP), has a central role in this regulation. Loss of CtBP from the BRCA1 promoter through estrogen induction, depletion by RNA interference or increased NAD+/NADH ratio leads to HDAC1 dismissal, elevated histone acetylation and increased BRCA1 transcription. The active control of chromatin marks, DNA accessibility and gene expression at the BRCA1 promoter by this 'metabolic switch' provides an important molecular link between caloric intake and tumor suppressor expression in mammary cells.

Links

PubMed Online version:10.1038/nsmb.1941

Keywords

Acetylation; Alcohol Oxidoreductases/genetics; Alcohol Oxidoreductases/physiology; BRCA1 Protein/genetics; BRCA1 Protein/metabolism; Cell Line, Tumor; DNA-Binding Proteins/genetics; DNA-Binding Proteins/physiology; Estradiol/pharmacology; Gene Expression Regulation/drug effects; Histone Deacetylase 1/metabolism; Histones/metabolism; Humans; Promoter Regions, Genetic; RNA/metabolism; RNA Interference

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:BRCA1

acts_upstream_of

GO:0051726: regulation of cell cycle

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CTBP1

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CTBP1

involved_in

GO:0031507: heterochromatin assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CTBP1

involved_in

GO:0031065: positive regulation of histone deacetylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CTBP1

involved_in

GO:0051726: regulation of cell cycle

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CTBP1

involved_in

GO:0090241: negative regulation of histone H4 acetylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CTBP1

involved_in

GO:0035067: negative regulation of histone acetylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BRCA1

involved_in

GO:0071158: positive regulation of cell cycle arrest

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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