Research Article: TP53 codon 72 polymorphism affects accumulation of mtDNA damage in human cells

Date Published: January 29, 2012

Publisher: Impact Journals LLC

Author(s): Serena Altilia, Aurelia Santoro, Davide Malagoli, Catia Lanzarini, Josué Adolfo Ballesteros Álvarez, Gianluca Galazzo, Donald Carl Porter, Paolina Crocco, Giuseppina Rose, Giuseppe Passarino, Igor Boris Roninson, Claudio Franceschi, Stefano Salvioli.

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Abstract

Human TP53 gene is characterised by a polymorphism at codon 72 leading to an Arginine-to-Proline (R/P) substitution. The two resulting p53 isoforms have a different subcellular localisation after stress (more nuclear or more mitochondrial for the P or R isoform, respectively). p53P72 variant is more efficient than p53R72 in inducing the expression of genes involved in nuclear DNA repair. Since p53 is involved also in mitochondrial DNA (mtDNA) maintenance, we wondered whether these p53 isoforms are associated with different accumulation of mtDNA damage. We observed that cells bearing p53R72 accumulate lower amount of mtDNA damage upon rotenone stress with respect to cells bearing p53P72, and that p53R72 co-localises with polymerase gamma more than p53P72. We also analysed the in vivo accumulation of heteroplasmy in a 300 bp fragment of mtDNA D-loop of 425 aged subjects. We observed that subjects with heteroplasmy higher than 5% are significantly less than expected in the p53R72/R72 group. On the whole, these data suggest that the polymorphism of TP53 at codon 72 affects the accumulation of mtDNA mutations, likely through the different ability of the two p53 isoforms to bind to polymerase gamma, and may contribute to in vivo accumulation of mtDNA mutations.

Partial Text

Mitochondrial DNA (mtDNA) is a small, double-stranded circular molecule of 16,569 bp that is contained in many copies inside mitochondria, packaged into multimeric complexes called nucleoids made up of proteins and nucleic acids [1]. MtDNA molecules are particularly exposed to the reactive oxygen species (ROS) that are formed by the incomeplete oxygen reduction due to electron leakage from the transport chain and therefore are very susceptible to oxidative damage as well as to other mutagenic lesions, also because of a limited capability of their repair systems [2].

mtDNA integrity tends to decrease with age, as demonstrated by the accumulation of point mutations and deletions in a variety of tissues during aging in humans, monkeys, and rodents [35,36]. The accumulation of somatic mtDNA mutations has likely a causative role in the aging of the organisms, as suggested by animal models such as the mutator mice lacking the proofreading activity of polymerase gamma (polg) [5,6,37]. Therefore, it is reasonable to hypothesise that factors impinging upon the stability of mtDNA can affect the rate of aging in animals and humans.

 

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