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Science 298 (5598): 1587-1592

Copyright © 2002 by the American Association for the Advancement of Science

Mechanisms of AIF-Mediated Apoptotic DNA Degradation in Caenorhabditis elegans

Xiaochen Wang,1* Chonglin Yang,1* Jijie Chai,2 Yigong Shi,2 Ding Xue1dagger

Apoptosis-inducing factor (AIF), a mitochondrial oxidoreductase, is released into the cytoplasm to induce cell death in response to apoptotic signals. However, the mechanisms underlying this process have not been resolved. We report that inactivation of the Caenorhabditis elegans AIF homolog wah-1 by RNA interference delayed the normal progression of apoptosis and caused a defect in apoptotic DNA degradation. WAH-1 localized in C. elegans mitochondria and was released into the cytosol and nucleus by the BH3-domain protein EGL-1 in a caspase (CED-3)-dependent manner. In addition, WAH-1 associated and cooperated with the mitochondrial endonuclease CPS-6/endonuclease G (EndoG) to promote DNA degradation and apoptosis. Thus, AIF and EndoG define a single, mitochondria-initiated apoptotic DNA degradation pathway that is conserved between C. elegans and mammals.

1 Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309, USA.
2 Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed. E-mail: ding.xue{at}

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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
Molecular Cloning and Characterization of a Human AIF-like Gene with Ability to Induce Apoptosis.
Q. Xie, T. Lin, Y. Zhang, J. Zheng, and J. A. Bonanno (2005)
J. Biol. Chem. 280, 19673-19681
   Abstract »    Full Text »    PDF »
Role of Caspases in Death and Survival of the Plaque Macrophage.
T. Q. Nhan, W. C. Liles, and S. M. Schwartz (2005)
Arterioscler Thromb Vasc Biol 25, 895-903
   Abstract »    Full Text »    PDF »
Cell Death Independent of Caspases: A Review.
L. E. Broker, F. A.E. Kruyt, and G. Giaccone (2005)
Clin. Cancer Res. 11, 3155-3162
   Abstract »    Full Text »    PDF »
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J. Takano, M. Tomioka, S. Tsubuki, M. Higuchi, N. Iwata, S. Itohara, M. Maki, and T. C. Saido (2005)
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   Abstract »    Full Text »    PDF »
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B. M. Polster, G. Basanez, A. Etxebarria, J. M. Hardwick, and D. G. Nicholls (2005)
J. Biol. Chem. 280, 6447-6454
   Abstract »    Full Text »    PDF »
Apoptosis-Inducing Factor Is a Key Factor in Neuronal Cell Death Propagated by BAX-Dependent and BAX-Independent Mechanisms.
E. C. C. Cheung, L. Melanson-Drapeau, S. P. Cregan, J. L. Vanderluit, K. L. Ferguson, W. C. McIntosh, D. S. Park, S. A. L. Bennett, and R. S. Slack (2005)
J. Neurosci. 25, 1324-1334
   Abstract »    Full Text »    PDF »
Apoptotic and autophagic cell death induced by histone deacetylase inhibitors.
Y. Shao, Z. Gao, P. A. Marks, and X. Jiang (2004)
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   Abstract »    Full Text »    PDF »
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D. N. Zacks, Q.-D. Zheng, Y. Han, R. Bakhru, and J. W. Miller (2004)
Invest. Ophthalmol. Vis. Sci. 45, 4563-4569
   Abstract »    Full Text »    PDF »
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N. Vahsen, C. Cande, J.-J. Briere, P. Benit, N. Joza, N. Larochette, P. G. Mastroberardino, M. O. Pequignot, N. Casares, V. Lazar, et al. (2004)
EMBO J. 23, 4679-4689
   Abstract »    Full Text »    PDF »
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Y. Fannjiang, W.-C. Cheng, S. J. Lee, B. Qi, J. Pevsner, J. M. McCaffery, R. B. Hill, G. Basanez, and J. M. Hardwick (2004)
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   Abstract »    Full Text »    PDF »
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Blood 104, 3233-3242
   Abstract »    Full Text »    PDF »
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M. T. Crow, K. Mani, Y.-J. Nam, and R. N. Kitsis (2004)
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   Abstract »    Full Text »    PDF »
Emerging Role for ERK as a Key Regulator of Neuronal Apoptosis.
E. C. C. Cheung and R. S. Slack (2004)
Sci. STKE 2004, pe45
   Abstract »    Full Text »    PDF »
Proteolysis of the Mismatch Repair Protein MLH1 by Caspase-3 Promotes DNA Damage-induced Apoptosis.
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J. Biol. Chem. 279, 27542-27548
   Abstract »    Full Text »    PDF »
`The stress of dying': the role of heat shock proteins in the regulation of apoptosis.
H. M. Beere (2004)
J. Cell Sci. 117, 2641-2651
   Abstract »    Full Text »    PDF »
The Caenorhabditis elegans pvl-5 Gene Protects Hypodermal Cells From ced-3-Dependent, ced-4-Independent Cell Death.
P. Joshi and D. M. Eisenmann (2004)
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   Abstract »    Full Text »    PDF »
Apoptotic Signaling Pathways Induced by Nitric Oxide in Human Lymphoblastoid Cells Expressing Wild-Type or Mutant p53.
C.-Q. Li, A. I. Robles, C. L. Hanigan, L. J. Hofseth, L. J. Trudel, C. C. Harris, and G. N. Wogan (2004)
Cancer Res. 64, 3022-3029
   Abstract »    Full Text »    PDF »
Methamphetamine induces neuronal apoptosis via cross-talks between endoplasmic reticulum and mitochondria-dependent death cascades.
FASEB J 18, 238-251
   Abstract »    Full Text »    PDF »
Endonuclease G is required for early embryogenesis and normal apoptosis in mice.
J. Zhang, M. Dong, L. Li, Y. Fan, P. Pathre, J. Dong, D. Lou, J. M. Wells, D. Olivares-Villagomez, L. Van Kaer, et al. (2003)
PNAS 100, 15782-15787
   Abstract »    Full Text »    PDF »
Mechanisms of Caspase-Independent Neuronal Death: Energy Depletion and Free Radical Generation.
I. C. J. Lang-Rollin, H. J. Rideout, M. Noticewala, and L. Stefanis (2003)
J. Neurosci. 23, 11015-11025
   Abstract »    Full Text »    PDF »
Chemosensitization by a Non-apoptogenic Heat Shock Protein 70-Binding Apoptosis-Inducing Factor Mutant.
E. Schmitt, A. Parcellier, S. Gurbuxani, C. Cande, A. Hammann, M. C. Morales, C. R. Hunt, D. J. Dix, R. T. Kroemer, F. Giordanetto, et al. (2003)
Cancer Res. 63, 8233-8240
   Abstract »    Full Text »    PDF »
RNA Interference in Biology and Medicine.
O. Milhavet, D. S. Gary, and M. P. Mattson (2003)
Pharmacol. Rev. 55, 629-648
   Abstract »    Full Text »    PDF »
HSP72 inhibits apoptosis-inducing factor release in ATP-depleted renal epithelial cells.
K. Ruchalski, H. Mao, S. K. Singh, Y. Wang, D. D. Mosser, F. Li, J. H. Schwartz, and S. C. Borkan (2003)
Am J Physiol Cell Physiol 285, C1483-C1493
   Abstract »    Full Text »    PDF »
Ways of dying: multiple pathways to apoptosis.
J. M. Adams (2003)
Genes & Dev. 17, 2481-2495
   Full Text »    PDF »
Real-time single cell analysis of Smac/DIABLO release during apoptosis.
M. Rehm, H. Dussmann, and J. H.M. Prehn (2003)
J. Cell Biol. 162, 1031-1043
   Abstract »    Full Text »    PDF »
Mitochondrial release of AIF and EndoG requires caspase activation downstream of Bax/Bak-mediated permeabilization.
D. Arnoult, B. Gaume, M. Karbowski, J. C. Sharpe, F. Cecconi, and R. J. Youle (2003)
EMBO J. 22, 4385-4399
   Abstract »    Full Text »    PDF »
Cathepsin D Triggers Bax Activation, Resulting in Selective Apoptosis-inducing Factor (AIF) Relocation in T Lymphocytes Entering the Early Commitment Phase to Apoptosis.
N. Bidere, H. K. Lorenzo, S. Carmona, M. Laforge, F. Harper, C. Dumont, and A. Senik (2003)
J. Biol. Chem. 278, 31401-31411
   Abstract »    Full Text »    PDF »
AIF: A Multifunctional Cog in the Life and Death Machine.
T. M. Hansen and P. Nagley (2003)
Sci. STKE 2003, pe31
   Abstract »    Full Text »    PDF »
Subunit Structures and Stoichiometries of Human DNA Fragmentation Factor Proteins before and after Induction of Apoptosis.
P. Widlak, J. Lanuszewska, R. B. Cary, and W. T. Garrard (2003)
J. Biol. Chem. 278, 26915-26922
   Abstract »    Full Text »    PDF »
CRN-1, a Caenorhabditis elegans FEN-1 homologue, cooperates with CPS-6/EndoG to promote apoptotic DNA degradation.
J. Z. Parrish, C. Yang, B. Shen, and D. Xue (2003)
EMBO J. 22, 3451-3460
   Abstract »    Full Text »    PDF »

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