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Structural basis for cell type specific DNA binding of C/EBPß: The case of cell cycle inhibitor p15INK4b promoter.
Lountos, George T; Cherry, Scott; Tropea, Joseph E; Wlodawer, Alexander; Miller, Maria.
Affiliation
  • Lountos GT; Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA. Electronic address: lountosg@mail.nih.gov.
  • Cherry S; Protein Purification Core, Center for Structural Biology, National Cancer Institute, Frederick, MD 21702-1201, USA.
  • Tropea JE; Protein Purification Core, Center for Structural Biology, National Cancer Institute, Frederick, MD 21702-1201, USA.
  • Wlodawer A; Protein Structure Section, Center for Structural Biology, National Cancer Institute, Frederick, MD 21702-1201 USA.
  • Miller M; Protein Structure Section, Center for Structural Biology, National Cancer Institute, Frederick, MD 21702-1201 USA.
J Struct Biol ; 214(4): 107918, 2022 12.
Article in En | MEDLINE | ID: mdl-36343842
C/EBPß is a key regulator of numerous cellular processes, but it can also contribute to tumorigenesis and viral diseases. It binds to specific DNA sequences (C/EBP sites) and interacts with other transcription factors to control expression of multiple eukaryotic genes in a tissue and cell-type dependent manner. A body of evidence has established that cell-type-specific regulatory information is contained in the local DNA sequence of the binding motif. In human epithelial cells, C/EBPß is an essential cofactor for TGFß signaling in the case of Smad2/3/4 and FoxO-dependent induction of the cell cycle inhibitor, p15INK4b. In the TGFß-responsive region 2 of the p15INK4b promoter, the Smad binding site is flanked by a C/EBP site, CTTAA•GAAAG, which differs from the canonical, palindromic ATTGC•GCAAT motif. The X-ray crystal structure of C/EBPß bound to the p15INK4b promoter fragment shows how GCGC-to-AAGA substitution generates changes in the intermolecular interactions in the protein-DNA interface that enhances C/EBPß binding specificity, limits possible epigenetic regulation of the promoter, and generates a DNA element with a unique pattern of methyl groups in the major groove. Significantly, CT/GA dinucleotides located at the 5'ends of the double stranded element maintain local narrowing of the DNA minor groove width that is necessary for DNA recognition. Our results suggest that C/EBPß would accept all forms of modified cytosine in the context of the CpT site. This contrasts with the effect on the consensus motif, where C/EBPß binding is modestly increased by cytosine methylation, but substantially decreased by hydroxymethylation.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: CCAAT-Enhancer-Binding Protein-beta / Epigenesis, Genetic Limits: Humans Language: En Journal: J Struct Biol Journal subject: BIOLOGIA MOLECULAR Year: 2022 Document type: Article Country of publication: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: CCAAT-Enhancer-Binding Protein-beta / Epigenesis, Genetic Limits: Humans Language: En Journal: J Struct Biol Journal subject: BIOLOGIA MOLECULAR Year: 2022 Document type: Article Country of publication: United States