Mutant p53 is a transcriptional co-factor that binds to G-rich regulatory regions of active genes and generates transcriptional plasticity.
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Mutant p53 is a transcriptional co-factor that binds to G-rich regulatory regions of active genes and generates transcriptional plasticity. / Quante, Timo; Otto, Benjamin; Brázdová, Marie; Kejnovská, Iva; Deppert, Wolfgang; Tolstonog, Genrich V.
in: CELL CYCLE, Jahrgang 11, Nr. 17, 17, 2012, S. 3290-3303.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Mutant p53 is a transcriptional co-factor that binds to G-rich regulatory regions of active genes and generates transcriptional plasticity.
AU - Quante, Timo
AU - Otto, Benjamin
AU - Brázdová, Marie
AU - Kejnovská, Iva
AU - Deppert, Wolfgang
AU - Tolstonog, Genrich V
PY - 2012
Y1 - 2012
N2 - The molecular mechanisms underlying mutant p53 (mutp53) "gain-of-function" (GOF) are still insufficiently understood, but there is evidence that mutp53 is a transcriptional regulator that is recruited by specialized transcription factors. Here we analyzed the binding sites of mutp53 and the epigenetic status of mutp53-regulated genes that had been identified by global expression profiling upon depletion of endogenous mutp53 (R273H) expression in U251 glioblastoma cells. We found that mutp53 preferentially and autonomously binds to G/C-rich DNA around transcription start sites (TSS) of many genes characterized by active chromatin marks (H3K4me3) and frequently associated with transcription-competent RNA polymerase II. Mutp53-bound regions overlap predominantly with CpG islands and are enriched in G4-motifs that are prone to form G-quadruplex structures. In line, mutp53 binds and stabilizes a well-characterized G-quadruplex structure in vitro. Hence, we assume that binding of mutp53 to G/C-rich DNA regions associated with a large set of cancer-relevant genes is an initial step in their regulation by mutp53. Using GAS1 and HTR2A as model genes, we show that mutp53 affects several parameters of active transcription. Finally, we discuss a dual mode model of mutp53 GOF, which includes both stochastic and deterministic components.
AB - The molecular mechanisms underlying mutant p53 (mutp53) "gain-of-function" (GOF) are still insufficiently understood, but there is evidence that mutp53 is a transcriptional regulator that is recruited by specialized transcription factors. Here we analyzed the binding sites of mutp53 and the epigenetic status of mutp53-regulated genes that had been identified by global expression profiling upon depletion of endogenous mutp53 (R273H) expression in U251 glioblastoma cells. We found that mutp53 preferentially and autonomously binds to G/C-rich DNA around transcription start sites (TSS) of many genes characterized by active chromatin marks (H3K4me3) and frequently associated with transcription-competent RNA polymerase II. Mutp53-bound regions overlap predominantly with CpG islands and are enriched in G4-motifs that are prone to form G-quadruplex structures. In line, mutp53 binds and stabilizes a well-characterized G-quadruplex structure in vitro. Hence, we assume that binding of mutp53 to G/C-rich DNA regions associated with a large set of cancer-relevant genes is an initial step in their regulation by mutp53. Using GAS1 and HTR2A as model genes, we show that mutp53 affects several parameters of active transcription. Finally, we discuss a dual mode model of mutp53 GOF, which includes both stochastic and deterministic components.
KW - Humans
KW - Cell Line, Tumor
KW - Gene Expression Profiling
KW - Chromatin Immunoprecipitation
KW - Polymerase Chain Reaction
KW - Mutation/genetics
KW - Gene Expression Regulation, Neoplastic/genetics
KW - Tumor Suppressor Protein p53/genetics/metabolism
KW - Binding Sites/genetics
KW - Cell Cycle Proteins/genetics/metabolism
KW - GPI-Linked Proteins/genetics/metabolism
KW - Guanosine/metabolism
KW - Receptor, Serotonin, 5-HT2A/genetics/metabolism
KW - Regulatory Elements, Transcriptional/genetics/physiology
KW - Transcription, Genetic/genetics
KW - Humans
KW - Cell Line, Tumor
KW - Gene Expression Profiling
KW - Chromatin Immunoprecipitation
KW - Polymerase Chain Reaction
KW - Mutation/genetics
KW - Gene Expression Regulation, Neoplastic/genetics
KW - Tumor Suppressor Protein p53/genetics/metabolism
KW - Binding Sites/genetics
KW - Cell Cycle Proteins/genetics/metabolism
KW - GPI-Linked Proteins/genetics/metabolism
KW - Guanosine/metabolism
KW - Receptor, Serotonin, 5-HT2A/genetics/metabolism
KW - Regulatory Elements, Transcriptional/genetics/physiology
KW - Transcription, Genetic/genetics
M3 - SCORING: Journal article
VL - 11
SP - 3290
EP - 3303
JO - CELL CYCLE
JF - CELL CYCLE
SN - 1538-4101
IS - 17
M1 - 17
ER -
