Deletion of p66shc in mice increases the frequency of size-change mutations in the lacZ transgene

Elena Beltrami, Antonella Ruggiero, Rita Busuttil, Enrica Migliaccio, Pier Giuseppe Pelicci, Jan Vijg, Marco Giorgio

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Upon oxidative challenge the genome accumulates adducts and breaks that activate the DNA damage response to repair, arrest, or eliminate the damaged cell. Thus, reactive oxygen species (ROS) generated by endogenous oxygen metabolism are thought to affect mutation frequency. However, few studies determined the mutation frequency when oxidative stress is reduced. To test whether in vivo spontaneous mutation frequency is altered in mice with reduced oxidative stress and cell death rate, we crossed p66Shc knockout (p66KO) mice, characterized by reduced intracellular concentration of ROS and by impaired apoptosis, with a transgenic line harboring multiple copies of the lacZ mutation reporter gene as part of a plasmid that can be recovered from organs into Escherichia coli to measure mutation rate. Liver and small intestine from 2- to 24-month-old, lacZ (p66Shc+/+) and lacZp66KO mice, were investigated revealing no difference in overall mutation frequency but a significant increase in the frequency of size-change mutations in the intestine of lacZp66KO mice. This differencewasfurther increaseduponirradiationof mice withX-ray. In addition,wefoundthatknockingdowncyclophilinD, a gene that facilitates mitochondrial apoptosis acting downstream of p66Shc, increased the size-change mutation frequency in small intestine. Size-change mutations also accumulated in death-resistantembryonic fibroblastsfrom lacZp66KOmice treatedwithH2O2. These results indicate that p66Shc plays a role in the accumulation of DNA rearrangements and suggest that p66Shc functions to clear damaged cells rather than affect DNA metabolism.

Original languageEnglish (US)
Pages (from-to)177-183
Number of pages7
JournalAging cell
Volume12
Issue number2
DOIs
StatePublished - Jan 11 2013

Keywords

  • Cell death
  • Longevity genes
  • Mice
  • Mitochondria
  • Mutagenesis
  • Reactive oxygen species

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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    Beltrami, E., Ruggiero, A., Busuttil, R., Migliaccio, E., Pelicci, P. G., Vijg, J., & Giorgio, M. (2013). Deletion of p66shc in mice increases the frequency of size-change mutations in the lacZ transgene. Aging cell, 12(2), 177-183. https://doi.org/10.1111/acel.12036