Essential roles for Fe65, Alzheimer amyloid precursor-binding protein, in the cellular response to DNA damage.
Fe65 interacts with the cytosolic domain of the Alzheimer amyloid precursor protein (APP). The functions of the Fe65 are still unknown. To address this point we generated Fe65 knockout (KO) mice. These mice do not show any obvious phenotype; however, when fibroblasts (mouse embryonic fibroblasts), isolated from Fe65 KO embryos, were exposed to low doses of DNA damaging agents, such as etoposide or H2O2, an increased sensitivity to genotoxic stress, compared with wild type animals, clearly emerged. Accordingly, brain extracts from Fe65 KO mice, exposed to non-lethal doses of ionizing radiations, showed high levels of gamma-H2AX and p53, thus demonstrating a higher sensitivity to X-rays than wild type mice. Nuclear Fe65 is necessary to rescue the observed phenotype, and few minutes after the exposure of MEFs to DNA damaging agents, Fe65 undergoes phosphorylation in the nucleus. With a similar timing, the proteolytic processing of APP is rapidly affected by the genotoxic stress: in fact, the cleavage of the APP COOH-terminal fragments by gamma-secretase is induced soon after the exposure of cells to etoposide, in a Fe65-dependent manner. These results demonstrate that Fe65 plays an essential role in the response of the cells to DNA damage.
Minopoli
Giuseppina
G
CEINGE Biotecnologie Avanzate, 80145 Napoli, Italy.
Stante
Maria
M
Napolitano
Francesco
F
Telese
Francesca
F
Aloia
Luigi
L
De Felice
Mario
M
Di Lauro
Roberto
R
Pacelli
Roberto
R
Brunetti
Arturo
A
Zambrano
Nicola
N
Russo
Tommaso
T
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001921:Brain / Q000502:physiology; D002467:Cell Nucleus / Q000502:physiology; D002478:Cells, Cultured; D004249:DNA Damage / Q000502:physiology*; D005047:Etoposide / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D006657:Histones / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology; D010641:Phenotype; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D000972:Antineoplastic Agents, Phytogenic; C486243:Apbb1 protein, mouse; D006657:Histones; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D016877:Oxidants; D016159:Tumor Suppressor Protein p53; C475961:gamma-H2AX protein, mouse; D005047:Etoposide; D006861:Hydrogen Peroxide