Abstract
G-quadruplexes are four-stranded nucleic acid structures that are implicated in the regulation of transcription, translation and replication. Genome regions enriched in putative G-quadruplex motifs include telomeres and gene promoters. Tumour suppressor p53 plays a critical role in regulatory pathways leading to cell cycle arrest, DNA repair and apoptosis. In addition to transcriptional regulation mediated via sequence-specific DNA binding, p53 can selectively bind various non-B DNA structures. In the present study, wild-type p53 (wtp53) binding to G-quadruplex formed by MYC promoter nuclease hypersensitive element (NHE) III1 region was investigated. Wtp53 binding to MYC G-quadruplex is comparable to interaction with specific p53 consensus sequence (p53CON). Apart from the full-length wtp53, its isolated C-terminal region (aa 320-393) as well, is capable of high-affinity MYC G-quadruplex binding, suggesting its critical role in this typeof interaction. Moreover, wtp53 binds to MYC promoter region containing putative G-quadruplex motif in two wtp53-expressing cell lines. The results suggest that wtp53 binding to G-quadruplexes can take part in transcriptional regulation of its target genes.
Highlights
G-quadruplexes belong to a group of non-canonical DNA structures with suggested participation in cellular processes such as regulation of transcription and replication
Wild-type p53 binds MYC parallel G-quadruplex To investigate wtp53 binding to G-quadruplex DNA by EMSA, G-quadruplexes formed by single-stranded oligonucleotides Pu52, Pu33 and Pu22 derived from the nuclease hypersensitive element (NHE) III1 region of the MYC gene promoter were selected
G-quadruplex formation of the MYC NHE III1 region derived oligonucleotides was examined by CD spectroscopy and dimethyl sulfate (DMS) footprinting
Summary
G-quadruplexes belong to a group of non-canonical DNA structures with suggested participation in cellular processes such as regulation of transcription and replication. Formation of G-quadruplexes in promoters has been proposed to serve a regulatory function where the G-quadruplex structure acts as a transcriptional modulator that can be targeted with potential anticancer drugs [5,6] Both repression and induction of genes via promoter G-quadruplex motif have been observed [7,8,9,10,11]. The 27-nt long Grich oligonucleotide Pu27 from the MYC NHE III1 region can form two major types of intramolecular G-quadruplexes with 1:2:1 or 1:6:1 loop arrangements, depending on which guanine tracts are involved in G-tetrad formation [17,18]. It has been suggested that under the conditions of negative superhelicity, the NHE III1 region can locally unwind and subsequently adopt a G-quadruplex/i-motif structure which can modulate protein binding and regulate gene expression [22]. We investigated wtp protein interaction with the MYC promoter G-quadruplex as this may participate in p53-mediated transcriptional regulation
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