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  • Original Article
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Physical interaction of apoptosis-inducing factor with DNA and RNA

Abstract

Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein, which upon apoptosis induction translocates to the nucleus where it interacts with DNA by virtue of positive charges clustered on the AIF surface. Here we show that the AIF interactome, as determined by mass spectroscopy, contains a large panel of ribonucleoproteins, which apparently bind to AIF through the RNA moiety. However, AIF is devoid of any detectable RNAse activity both in vitro and in vivo. Recombinant AIF can directly bind to DNA as well as to RNA. This binding can be visualized by electron microscopy, revealing that AIF can condense DNA, showing a preferential binding to single-stranded over double-stranded DNA. AIF also binds and aggregates single-stranded and structured RNA in vitro. Single-stranded poly A, poly G and poly C, as well double-stranded A/T and G/C RNA competed with DNA for AIF binding with a similar efficiency, thus corroborating a computer-calculated molecular model in which the binding site within AIF is the same for distinct nucleic acid species, without a clear sequence specificity. Among the preferred electron donors and acceptors of AIF, nicotine adenine dinucleotide phosphate (NADP) was particularly efficient in enhancing the generation of higher-order AIF/DNA and AIF/RNA complexes. Altogether, these data support a model in which a direct interaction of AIF contributes to the compaction of nucleic acids within apoptotic cells.

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Accession codes

Accessions

GenBank/EMBL/DDBJ

Abbreviations

AIF:

apoptosis-inducing factor

NAD:

nicotine adenine dinucleotide

NADP:

nicotine adenine dinucleotide phosphate

TEM:

transmission electron microscopy

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Acknowledgements

We thank Nathanael Larochette and Didier Métivier for expert technical assistance. This work was supported by a special grant of the French League against Cancers as well as by grants by the European Union (Trans-Death, Right, Impaled) (to GK), Agence Nationale pour la Recherche sur le SIDA, Association pour la Recherche sur le cancer and the League against Cancer (to ELC). NV received a fellowship from the Association pour la Recherche sur le Cancer.

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Correspondence to G Kroemer.

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Vahsen, N., Candé, C., Dupaigne, P. et al. Physical interaction of apoptosis-inducing factor with DNA and RNA. Oncogene 25, 1763–1774 (2006). https://doi.org/10.1038/sj.onc.1209206

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