Modulation of gene expression in U251 glioblastoma cells by binding of mutant p53 R273H to intronic and intergenic sequences
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Modulation of gene expression in U251 glioblastoma cells by binding of mutant p53 R273H to intronic and intergenic sequences. / Brázdová, Marie; Quante, Timo; Tögel, Lars; Walter, Korden; Loscher, Christine; Tichý, Vlastimil; Cincárová, Lenka; Deppert, Wolfgang; Tolstonog, Genrich V.
In: NUCLEIC ACIDS RES, Vol. 37, No. 5, 04.2009, p. 1486-500.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Modulation of gene expression in U251 glioblastoma cells by binding of mutant p53 R273H to intronic and intergenic sequences
AU - Brázdová, Marie
AU - Quante, Timo
AU - Tögel, Lars
AU - Walter, Korden
AU - Loscher, Christine
AU - Tichý, Vlastimil
AU - Cincárová, Lenka
AU - Deppert, Wolfgang
AU - Tolstonog, Genrich V
PY - 2009/4
Y1 - 2009/4
N2 - Missense point mutations in the TP53 gene are frequent genetic alterations in human tumor tissue and cell lines derived thereof. Mutant p53 (mutp53) proteins have lost sequence-specific DNA binding, but have retained the ability to interact in a structure-selective manner with non-B DNA and to act as regulators of transcription. To identify functional binding sites of mutp53, we established a small library of genomic sequences bound by p53(R273H) in U251 human glioblastoma cells using chromatin immunoprecipitation (ChIP). Mutp53 binding to isolated DNA fragments confirmed the specificity of the ChIP. The mutp53 bound DNA sequences are rich in repetitive DNA elements, which are dispersed over non-coding DNA regions. Stable down-regulation of mutp53 expression strongly suggested that mutp53 binding to genomic DNA is functional. We identified the PPARGC1A and FRMD5 genes as p53(R273H) targets regulated by binding to intronic and intra-genic sequences. We propose a model that attributes the oncogenic functions of mutp53 to its ability to interact with intronic and intergenic non-B DNA sequences and modulate gene transcription via re-organization of chromatin.
AB - Missense point mutations in the TP53 gene are frequent genetic alterations in human tumor tissue and cell lines derived thereof. Mutant p53 (mutp53) proteins have lost sequence-specific DNA binding, but have retained the ability to interact in a structure-selective manner with non-B DNA and to act as regulators of transcription. To identify functional binding sites of mutp53, we established a small library of genomic sequences bound by p53(R273H) in U251 human glioblastoma cells using chromatin immunoprecipitation (ChIP). Mutp53 binding to isolated DNA fragments confirmed the specificity of the ChIP. The mutp53 bound DNA sequences are rich in repetitive DNA elements, which are dispersed over non-coding DNA regions. Stable down-regulation of mutp53 expression strongly suggested that mutp53 binding to genomic DNA is functional. We identified the PPARGC1A and FRMD5 genes as p53(R273H) targets regulated by binding to intronic and intra-genic sequences. We propose a model that attributes the oncogenic functions of mutp53 to its ability to interact with intronic and intergenic non-B DNA sequences and modulate gene transcription via re-organization of chromatin.
KW - Binding Sites
KW - Cell Line, Tumor
KW - Chromatin
KW - Chromatin Immunoprecipitation
KW - DNA, Intergenic
KW - Gene Expression Regulation, Neoplastic
KW - Genes, p53
KW - Genome, Human
KW - Glioblastoma
KW - Humans
KW - Introns
KW - Mutation, Missense
KW - Sequence Analysis, DNA
KW - Tumor Suppressor Protein p53
U2 - 10.1093/nar/gkn1085
DO - 10.1093/nar/gkn1085
M3 - SCORING: Journal article
C2 - 19139068
VL - 37
SP - 1486
EP - 1500
JO - NUCLEIC ACIDS RES
JF - NUCLEIC ACIDS RES
SN - 0305-1048
IS - 5
ER -