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 knock out (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 E. coli to measure mutation rate. Liver and small intestine from 2- and 24- month old, lacZ (p66Shc+/+) and lacZp66KO mice, were investigated revealing no difference in overall mutation frequency but a significant increase of the frequency of size-change mutations in the intestine of lacZp66KO mice. This difference was further increased upon irradiation of mice with X-Ray. Additionally, we found that knocking down cyclophilin D, 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-resistant embryonic fibroblasts from lacZp66KO mice treated with H(2) O(2.) 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. © 2012 The Authors Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.
Deletion of p66Shc in mice increases the frequency of size-change mutations in the lacZ transgene / E. Beltrami, A. Ruggiero, R. Busuttil, E. Migliaccio, P.G. Pelicci, J. Vijg, M. Giorgio. - In: AGING CELL. - ISSN 1474-9718. - 12:2(2013 Apr), pp. 177-183.
|Titolo:||Deletion of p66Shc in mice increases the frequency of size-change mutations in the lacZ transgene|
BELTRAMI, ELENA (Primo)
|Parole Chiave:||Cell death; Longevity genes; Mice; Mitochondria; Mutagenesis; Reactive oxygen species|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Data di pubblicazione:||apr-2013|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1111/acel.12036|
|Appare nelle tipologie:||01 - Articolo su periodico|