Minopoli G, Stante M, Napolitano F, Telese F, Aloia L, De Felice M, Di Lauro R, Pacelli R, Brunetti A, Zambrano N, Russo T. Essential roles for Fe65, Alzheimer amyloid precursor-binding protein, in the cellular response to DNA damage. J Biol Chem. 2007 Jan 12;282(2):831-5. PubMed.
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This is an interesting study showing that loss of Fe65 increases susceptibility to DNA damage in vitro and in vivo. The increased susceptibility to DNA damage could only be rescued by nuclear Fe65 expression in Fe65 MEF KO cells and was associated with accumulation of a subset of nuclear Fe65 isoforms. In addition, decreased levels of the APP-CTF C83 were observed upon etoposide treatment. This decrease was blocked by treatment with a γ-secretase inhibitor and was not observed in an Fe65 KO MEF line, suggesting that Fe65 is required for increased processing of C83 under these conditions.
Several questions remain to be answered about the mechanism by which Fe65 modulates the cellular response to DNA damaging agents, particularly as it relates to the Fe65/APP interactions, because this may contribute to the increased incidence of DNA damage observed in AD brains.
1. There are two recent reports that support a role for AICD-dependent regulation of p53 expression and activity (Alves da Costa et al., 2006; Ozaki et al., 2006). It would be interesting to know whether the decrease in APP-CTF following etoposide treatment in WT MEF cells is associated with an increase in membrane or nuclear AICD, possibly identifying a cellular event leading to regulated generation of AICD. Alternatively, the decrease in APP-CTF may be due to caspase cleavage initiated by the etoposide treatment.
2. The data show that Fe65 is required for the transient decrease in C83 upon etoposide treatment. Since Fe65 has been reported to influence APP trafficking, it is possible that etoposide treatment transiently affects Fe65-dependent APP-CTF trafficking and processing.
3. If modulation of the APP/Fe65 interaction impacts DNA damage, APP KO MEFs treated with etoposide may also show increased susceptibility to DNA damage.
4. Fe65 was previously shown in the Russo lab to bind SET (Telese et al., 2005), a protein that can block the single-strand DNA-nicking activity of NM23-H1 (Fan et al., 2003; Zhao et al., 2006). Increased single-stranded DNA nicking has been observed when NM23-H1 is activated after degradation of its inhibitor, SET, in the nucleus (Fan et al., 2003; Zhao et al., 2006). SET also binds a caspase-derived C-terminal APP peptide (aa 649-664 of APP695), Jcasp, capable of inducing cell death. Decreasing SET expression blocks Jcasp-induced cell death (Madeira et al., 2005). Does loss of Fe65 affect SET stability and/or its subcellular localization, thus sensitizing cells to DNA damage?
References:
Alves DA Costa C, Sunyach C, Pardossi-Piquard R, Sévalle J, Vincent B, Boyer N, Kawarai T, Girardot N, St George-Hyslop P, Checler F. Presenilin-dependent gamma-secretase-mediated control of p53-associated cell death in Alzheimer's disease. J Neurosci. 2006 Jun 7;26(23):6377-85. PubMed.
Fan Z, Beresford PJ, Oh DY, Zhang D, Lieberman J. Tumor suppressor NM23-H1 is a granzyme A-activated DNase during CTL-mediated apoptosis, and the nucleosome assembly protein SET is its inhibitor. Cell. 2003 Mar 7;112(5):659-72. PubMed.
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Ozaki T, Li Y, Kikuchi H, Tomita T, Iwatsubo T, Nakagawara A. The intracellular domain of the amyloid precursor protein (AICD) enhances the p53-mediated apoptosis. Biochem Biophys Res Commun. 2006 Dec 8;351(1):57-63. PubMed.
Telese F, Bruni P, Donizetti A, Gianni D, D'Ambrosio C, Scaloni A, Zambrano N, Rosenfeld MG, Russo T. Transcription regulation by the adaptor protein Fe65 and the nucleosome assembly factor SET. EMBO Rep. 2005 Jan;6(1):77-82. PubMed.
Zhao T, Zhang H, Guo Y, Zhang Q, Hua G, Lu H, Hou Q, Liu H, Fan Z. Granzyme K cleaves the nucleosome assembly protein SET to induce single-stranded DNA nicks of target cells. Cell Death Differ. 2007 Mar;14(3):489-99. PubMed.
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