Essential roles for Fe65, Alzheimer amyloid precursor-binding protein, in the cellular response to DNA damage(1010 views) Minopoli G, Stante M, Napolitano F, Telese F, Aloia L, De Felice M, Di Lauro R, Pacelli R, Brunetti A, Zambrano N, Russo T
CEINGE Biotecnologie Avanzate, 80145 Napoli, Italy
Dipartimento di Biochimica e Biotecnologie Mediche, Università di Napoli Federico II, 80131 Napoli, Italy
BioGeM Scarl-CEINGE, 80145 Napoli, Italy
Istituto di Biostrutture e Bioimmagini, CNR, Università di Napoli Federico II, 80131 Napoli, Italy
SEMM, European School of Molecular Medicine, Italy
University Campus Bio-Medico, Rome, Italy
Italian National Research Center on Aging, Cosenza, Italy
Federico II University School of Medicine, Naples, Italy
Viale della Resistenza Pal. Alfa Scala H, I-87036 Rende (CS), Italy
Department of Clinical Science and Bioimaging, Section of Radiology, University of Chieti, via dei Vestini, Chieti 66013, Italy
Department of Bioimaging and Radiological Sciences, Catholic University of Rome, Italy
References: Not available.
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.
Essential roles for Fe65, Alzheimer amyloid precursor-binding protein, in the cellular response to DNA damage