tumor suppressor p53 binds with high affinity to CTG.CAG trinucleotide repeats and induces topological alterations in mismatched duplexes.
DNA binding is central to the ability of p53 to function as a tumor suppressor. In line with the remarkable functional versatility of p53, which can act on DNA as a transcription, repair, recombination, replication, and chromatin accessibility factor, the modes of p53 interaction with DNA are also versatile. One feature common to all modes of p53-DNA interaction is the extraordinary sensitivity of p53 to the topology of its target DNA. Whereas the strong impact of DNA topology has been demonstrated for p53 binding to sequence-specific sites or to DNA lesions, the possibility that DNA structure-dependent recognition may underlie p53 interaction with other types of DNA has not been addressed until now. We demonstrate for the first time that conformationally flexible CTG.CAG trinucleotide repeats comprise a novel class of p53-binding sites targeted by p53 in a DNA structure-dependent mode in vitro and in vivo. Our major finding is that p53 binds to CTG.CAG tracts by different modes depending on the conformation of DNA. Although p53 binds preferentially to hairpins formed by either CTG or CAG strands, it can also bind to linear forms of CTG.CAG tracts such as canonic B DNA or mismatched duplex. Intriguingly, by binding to a mismatched duplex p53 can induce further topological alterations in DNA, indicating that p53 may act as a DNA topology-modulating factor.
Walter
Korden
K
Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie, Martinistrasse 52, D-20251, Hamburg, Germany.
Warnecke
Gabriele
G
Bowater
Richard
R
Deppert
Wolfgang
W
Kim
Ella
E
D020137:Base Pair Mismatch; D001665:Binding Sites; D045744:Cell Line, Tumor; D002843:Chromatin / Q000737:chemistry; D047369:Chromatin Immunoprecipitation; D003001:Cloning, Molecular; D004247:DNA / Q000737:chemistry*; D004277:DNA, Single-Stranded / Q000235:genetics; D003851:Deoxyribonucleases / Q000737:chemistry; D017930:Genes, Reporter; D016158:Genes, p53; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008968:Molecular Conformation; D009690:Nucleic Acid Conformation; D009841:Oligonucleotides / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D014162:Transfection; D018911:Trinucleotide Repeats; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics*
D002843:Chromatin; D004277:DNA, Single-Stranded; D009841:Oligonucleotides; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D004247:DNA; D008156:Luciferases; D003851:Deoxyribonucleases