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Brief Definitive Report

^a Centre National de la Recherche Scientifique, UMR1599, Institut Gustave Roussy, F-94805 Villejuif, France
^b Assistance Publique — Hôpitaux de Paris, Service de Néphrologie B, Hôpital Tenon, F-75020 Paris, France
^c University of Edinburgh, Institute for Cellular and Molecular Biology, Edinburgh EH93JR, Midlothian, Scotland
^d Institut National de la Santé et de la Recherche Médicale U430, Hôpital Broussais, F-75014 Paris, France
^e Unité d'Oncologie Virale, Institut Pasteur, F-75015 Paris, France
^f The Amgen Institute and Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario M5G 2C1, Canada
CNRS-UMR1599, Institut Gustave Roussy, Pavillon de Recherche 1, 39, Rue Camille Desmoulins, 94805 Villejuif, France.33-1-42-11-60-46

Apaf-1^–/– or caspase-3^–/– cells treated with a variety of apoptosis inducers manifest apoptosis-associated alterations including the translocation of apoptosis-inducing factor (AIF) from mitochondria to nuclei, large scale DNA fragmentation, and initial chromatin condensation (stage I). However, when compared with normal control cells, Apaf-1^–/– or caspase-3^–/– cells fail to exhibit oligonucleosomal chromatin digestion and a more advanced pattern of chromatin condensation (stage II). Microinjection of such cells with recombinant AIF only causes peripheral chromatin condensation (stage I), whereas microinjection with activated caspase-3 or its downstream target caspase-activated DNAse (CAD) causes a more pronounced type of chromatin condensation (stage II). Similarly, when added to purified HeLa nuclei, AIF causes stage I chromatin condensation and large-scale DNA fragmentation, whereas CAD induces stage II chromatin condensation and oligonucleosomal DNA degradation. Furthermore, in a cell-free system, concomitant neutralization of AIF and CAD is required to suppress the nuclear DNA loss caused by cytoplasmic extracts from apoptotic wild-type cells. In contrast, AIF depletion alone suffices to suppress the nuclear DNA loss contained in extracts from apoptotic Apaf-1^–/– or caspase-3^–/– cells. As a result, at least two redundant parallel pathways may lead to chromatin processing during apoptosis. One of these pathways involves Apaf-1 and caspases, as well as CAD, and leads to oligonucleosomal DNA fragmentation and advanced chromatin condensation. The other pathway, which is caspase-independent, involves AIF and leads to large-scale DNA fragmentation and peripheral chromatin condensation.

Key Words: apoptosis-inducing factor • Apaf-1 • chromatin condensation • caspases • caspase-activated DNase

© 2000 The Rockefeller University Press

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