Research Paper Volume 4, Issue 1 pp 28—39

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

Serena Altilia 1, 2, , Aurelia Santoro 1, 3, , Davide Malagoli 4, , Catia Lanzarini 1, , Josué Adolfo Ballesteros Álvarez 1, , Gianluca Galazzo 1, , Donald Carl Porter 5, , Paolina Crocco 6, , Giuseppina Rose 6, , Giuseppe Passarino 6, , Igor Boris Roninson 7, , Claudio Franceschi 1, 3, , Stefano Salvioli 1, 3, ,

  • 1 Department of Experimental Pathology, University of Bologna, Bologna, 40126, Italy
  • 2 Ordway Research Institute, Albany NY 12208, USA
  • 3 Interdepartmental Centre “L. Galvani” (C.I.G.), University of Bologna, Bologna, 40126, Italy
  • 4 Department of Animal Biology, University of Modena and Reggio Emilia, Modena, 41100, Italy
  • 5 Senex Biotechnology, Inc., CLS Building, Columbia SC 29208, USA
  • 6 Department of Cell Biology, University of Calabria, Rende, 87030, Italy
  • 7 Department of Pharmaceutical and Biomedical Sciences, University of South Carolina, Columbia SC 29208

received: January 22, 2012 ; accepted: January 27, 2012 ; published: January 29, 2012 ;

https://doi.org/10.18632/aging.100425
How to Cite

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.

Abbreviations

ROS: reactive oxygen species; WBC: white blood cells; Polg: polymerase gamma; 8-oxo-dG: 8-hydroxy-2'-deoxyguanosine; mtDNA: mitochondrial DNA; mtDNA CR: mitochondrial DNA control region.