Journal Article

<i>G-quadruplex</i> structures in <i>TP53</i> intron 3: role in alternative splicing and in production of p53 mRNA isoforms

Virginie Marcel, Phong L.T. Tran, Charlotte Sagne, Ghyslaine Martel-Planche, Laurence Vaslin, Marie-Paule Teulade-Fichou, Janet Hall, Jean-Louis Mergny, Pierre Hainaut and Eric Van Dyck

in Carcinogenesis

Volume 32, issue 3, pages 271-278
Published in print March 2011 | ISSN: 0143-3334
Published online November 2010 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgq253
G-quadruplex structures in TP53 intron 3: role in alternative splicing and in production of p53 mRNA isoforms

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The tumor suppressor gene TP53, encoding p53, is expressed as several transcripts. The fully spliced p53 (FSp53) transcript encodes the canonical p53 protein. The alternatively spliced p53I2 transcript retains intron 2 and encodes Δ40p53 (or ΔNp53), an isoform lacking first 39 N-terminal residues corresponding to the main transactivation domain. We demonstrate the formation of G-quadruplex structures (G4) in a GC-rich region of intron 3 that modulates the splicing of intron 2. First, we show the formation of G4 in synthetic RNAs encompassing intron 3 sequences by ultraviolet melting, thermal difference spectra and circular dichroism spectroscopy. These observations are confirmed by detection of G4-induced reverse transcriptase elongation stops in synthetic RNA of intron 3. In this region, p53 pre-messenger RNA (mRNA) contains a succession of short exons (exons 2 and 3) and introns (introns 2 and 4) covering a total of 333 bp. Site-directed mutagenesis of G-tracts putatively involved in G4 formation decreased by ∼30% the excision of intron 2 in a green fluorescent protein-reporter splicing assay. Moreover, treatment of lymphoblastoid cells with 360A, a synthetic ligand that binds to single-strand G4 structures, increases the formation of FSp53 mRNA and decreases p53I2 mRNA expression. These results indicate that G4 structures in intron 3 regulate the splicing of intron 2, leading to differential expression of transcripts encoding distinct p53 isoforms.

Journal Article.  5279 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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