POTENTIAL MECHANISM RESPONSIBLE FOR HIGHER EXPRESSION OF TP53 MUTATED ALLELE
Marta Winiecka, Ewelina Stoczynska-Fidelus, Małgorzata Szybka, Michal Bienkowski, Maciej Walczak, Sylwester Piaskowski, Mateusz Banaszczyk, Krystyna Hulas-Bigoszewska and Piotr Rieske
Department of Tumour Biology, Medical University of Lodz, Poland
Although TP53 is known for 30 years, many questions regarding the function of this gene still remains unclear. Surprisingly, during sequencing, we noticed discrepancies between TP53 cDNA and DNA sequence – we detected the lack or trace of normal cDNA, and heterozygous mutation pattern during DNA analysis. Thus, we hypothesized that there is a mechanism responsible for a different expression of TP53 alleles. We found that some mechanism or structure can change the topology of mRNA from mutated allele or, that one of TP53 alleles are preferentially mutated due to some reasons. It was suggested that G-quadruplex structure in intron 3 can modulate TP53 mRNA modifications. Another important consideration with respect to the potential effect of G-quadruplex in intron 3 is that they include guanine residues – a part of a common polymorphism, TP53 PIN3, associated with higher risk of cancer. PIN3 variants may change the topology of G-quadruplexes in intron 3, therefore modify the TP53 mRNA. We decided to determine the role mentioned mechanism in TP53 mRNA expression in tumor specimens. In all analyzed cases, which showed PIN3 heterozygosity, TP53 heterozygous mutation and the lack or trace of normal cDNA, PIN3 allele with 16 bp duplication was mutated. Thus, mutation of this allele prevents normal TP53 activity despite the presence of wild-type allele, causes a definite predominance of mutated mRNA, and finally, can be partially responsible for the presence of TP53 heterozygous mutations. However, the extent of possible impact of 16 bp duplication and it consequence for mRNA expression remains to be investigated.
This study was supported by the National Science Center Grant No. 2011/01/B/NZ1/01502.