Abstract
DNA fragmentation is a critical component of apoptosis but it has not been characterized in nonapoptotic forms of cell death, such as necrosis and autophagic cell death. In mammalian apoptosis, caspase-activated DNase cleaves DNA into nucleosomal fragments in dying cells, and subsequently DNase II, an acid nuclease, completes the DNA degradation but acts non-cell autonomously within lysosomes of engulfing cells. Here we examine the requirement for DNases during two examples of programmed cell death (PCD) that occurs in the Drosophila melanogaster ovary, starvation-induced death of mid-stage egg chambers and developmental nurse cell death in late oogenesis. Surprisingly, we found that DNaseII was required cell autonomously in nurse cells during developmental PCD, indicating that it acts within dying cells. Dying nurse cells contain autophagosomes, indicating that autophagy may contribute to these forms of PCD. Furthermore, we provide evidence that developmental nurse cell PCD in late oogenesis shows hallmarks of necrosis. These findings indicate that DNaseII can act cell autonomously to degrade DNA during nonapoptotic cell death.
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Abbreviations
- Atg :
-
autophagy-specific gene
- CAD:
-
caspase-activated DNase
- cathD :
-
cathepsin D
- CP1:
-
cysteine proteinase-1
- DAPI:
-
4′,6-diamidino-2-phenylindole
- Df:
-
deficiency
- dor :
-
deep orange
- EM:
-
electron microscopy
- endo G:
-
endonuclease G
- FC:
-
follicle cell
- FLP:
-
FLIP recombinase
- FRT:
-
FLP recombination target
- GFP:
-
green fluorescent protein
- GLC:
-
germline clone
- ICAD:
-
inhibitor of caspase-activated DNase
- LC3:
-
microtubule-associated protein 1 light chain 3
- NC:
-
nurse cell
- LT:
-
LysoTracker
- NGT :
-
nanos-gal4-tubulin
- NUC-1:
-
abnormal nuclease-1
- PCD:
-
programmed cell death
- spin :
-
spinster
- st:
-
stage
- TUNEL:
-
terminal deoxynucleotidyl transferase dUTP nick-end labeling
- UAS:
-
upstream activating sequence
- w :
-
white
References
Vaux DL, Korsmeyer SJ . Cell death in development. Cell 1999; 96: 245–254.
Thompson CB . Apoptosis in the pathogenesis and treatment of disease. Science 1995; 267: 1456–1462.
Kroemer G, Galluzzi L, Vandenabeele P, Abrams J, Alnemri ES, Baehrecke EH et al. Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ 2009; 16: 3–11.
Nagata S . DNA degradation in development and programmed cell death. Annu Rev Immunol 2005; 23: 853–875.
Parrish JZ, Xue D . Cuts can kill: the roles of apoptotic nucleases in cell death and animal development. Chromosoma 2006; 115: 89–97.
Wu YC, Stanfield GM, Horvitz HR . NUC-1, a Caenorhabditis elegans DNase II homolog, functions in an intermediate step of DNA degradation during apoptosis. Genes Dev 2000; 14: 536–548.
Evans CJ, Merriam JR, Aguilera RJ . Drosophila acid DNase is a homolog of mammalian DNase II. Gene 2002; 295: 61–70.
Mukae N, Yokoyama H, Yokokura T, Sakoyama Y, Nagata S . Activation of the innate immunity in Drosophila by endogenous chromosomal DNA that escaped apoptotic degradation. Genes Dev 2002; 16: 2662–2671.
Seong CS, Varela-Ramirez A, Aguilera RJ . DNase II deficiency impairs innate immune function in Drosophila. Cell Immunol 2006; 240: 5–13.
Stone JC, Dower NA, Hauseman J, Cseko YM, Sederoff R . The characterization of a mutant affecting DNA metabolism in the development of D. melanogaster. Can J Genet Cytol 1983; 25: 129–138.
Mukae N, Yokoyama H, Yokokura T, Sakoyama Y, Sakahira H, Nagata S . Identification and developmental expression of inhibitor of caspase-activated DNase (ICAD) in Drosophila melanogaster. J Biol Chem 2000; 275: 21402–21408.
McCall K . Eggs over easy: cell death in the Drosophila ovary. Dev Biol 2004; 274: 3–14.
King RC . Ovarian Development in Drosophila Melanogaster. Academic Press: New York, 1970.
Drummond-Barbosa D, Spradling AC . Stem cells and their progeny respond to nutritional changes during Drosophila oogenesis. Dev Biol 2001; 231: 265–278.
Peterson JS, Barkett M, McCall K . Stage-specific regulation of caspase activity in Drosophila oogenesis. Dev Biol 2003; 260: 113–123.
Baum JS, Arama E, Steller H, McCall K . The Drosophila caspases Strica and Dronc function redundantly in programmed cell death during oogenesis. Cell Death Differ 2007; 14: 1508–1517.
Mazzalupo S, Cooley L . Illuminating the role of caspases during Drosophila oogenesis. Cell Death Differ 2006; 13: 1950–1959.
Velentzas AD, Nezis IP, Stravopodis DJ, Papassideri IS, Margaritis LH . Apoptosis and autophagy function cooperatively for the efficacious execution of programmed nurse cell death during Drosophila virilis oogenesis. Autophagy 2007; 3: 130–132.
Hou YC, Chittaranjan S, Barbosa SG, McCall K, Gorski SM . Effector caspase Dcp-1 and IAP protein Bruce regulate starvation-induced autophagy during Drosophila melanogaster oogenesis. J Cell Biol 2008; 182: 1127–1139.
Nezis IP, Lamark T, Velentzas AD, Rusten TE, Bjorkoy G, Johansen T et al. Cell death during Drosophila melanogaster early oogenesis is mediated through autophagy. Autophagy 2009; 5: 298–302.
Grell EH . Genetics of some deoxyribonucleases of Drosophila melanogaster. Genetics 1976; 83: s28–s29.
Peterson JS, Bass BP, Jue D, Rodriguez A, Abrams JM, McCall K . Noncanonical cell death pathways act during Drosophila oogenesis. Genesis 2007; 45: 396–404.
Chou TB, Perrimon N . The autosomal FLP-DFS technique for generating germline mosaics in Drosophila melanogaster. Genetics 1996; 144: 1673–1679.
Lindmo K, Simonsen A, Brech A, Finley K, Rusten TE, Stenmark H . A dual function for Deep orange in programmed autophagy in the Drosophila melanogaster fat body. Exp Cell Res 2006; 312: 2018–2027.
Sevrioukov EA, He JP, Moghrabi N, Sunio A, Kramer H . A role for the deep orange and carnation eye color genes in lysosomal delivery in Drosophila. Mol Cell 1999; 4: 479–486.
Sweeney ST, Davis GW . Unrestricted synaptic growth in spinster – a late endosomal protein implicated in TGF-beta-mediated synaptic growth regulation. Neuron 2002; 36: 403–416.
Nakano Y, Fujitani K, Kurihara J, Ragan J, Usui-Aoki K, Shimoda L et al. Mutations in the novel membrane protein Spinster interfere with programmed cell death and cause neural degeneration in Drosophila melanogaster. Mol Cell Biol 2001; 21: 3775–3788.
Scott RC, Schuldiner O, Neufeld TP . Role and regulation of starvation-induced autophagy in the Drosophila fat body. Dev Cell 2004; 7: 167–178.
Golstein P, Kroemer G . Cell death by necrosis: towards a molecular definition. Trends Biochem Sci 2007; 32: 37–43.
Klionsky DJ, Abeliovich H, Agostinis P, Agrawal DK, Aliev G, Askew DS et al. Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy 2008; 4: 151–175.
Rusten TE, Lindmo K, Juhasz G, Sass M, Seglen PO, Brech A et al. Programmed autophagy in the Drosophila fat body is induced by ecdysone through regulation of the PI3K pathway. Dev Cell 2004; 7: 179–192.
Rusten TE, Vaccari T, Lindmo K, Rodahl LM, Nezis IP, Sem-Jacobsen C et al. ESCRTs and Fab1 regulate distinct steps of autophagy. Curr Biol 2007; 17: 1817–1825.
Matova N, Mahanjan-Miklos S, Mooseker MS, Cooley L . Drosophila quail, a villin-related protein, bundles actin filaments in apoptotic nurse cells. Development 1999; 126: 5645–5657.
Nishimoto S, Kawane K, Watanabe-Fukunaga R, Fukuyama H, Ohsawa Y, Uchiyama Y et al. Nuclear cataract caused by a lack of DNA degradation in the mouse eye lens. Nature 2003; 424: 1071–1074.
Nakahara M, Nagasaka A, Koike M, Uchida K, Kawane K, Uchiyama Y et al. Degradation of nuclear DNA by DNase II-like acid DNase in cortical fiber cells of mouse eye lens. FEBS J 2007; 274: 3055–3064.
Counis MF, Torriglia A . Acid DNases and their interest among apoptotic endonucleases. Biochimie 2006; 88: 1851–1858.
Myllykangas L, Tyynela J, Page-McCaw A, Rubin GM, Haltia MJ, Feany MB . Cathepsin D-deficient Drosophila recapitulate the key features of neuronal ceroid lipofuscinoses. Neurobiol Dis 2005; 19: 194–199.
Buszczak M, Paterno S, Lighthouse D, Bachman J, Planck J, Owen S et al. The Carnegie protein trap library: a versatile tool for Drosophila developmental studies. Genetics 2007; 175: 1505–1531.
Frydman HM, Spradling AC . The receptor-like tyrosine phosphatase Lar is required for epithelial planar polarity and for axis determination within Drosophila ovarian follicles. Development 2001; 128: 3209–3220.
Acknowledgements
We thank Shigekazu Nagata, Daisuke Yamamoto, Tom Neufeld, Mel Feany, Tor Erik Rusten, Harald Stenmark, the FlyTrap Collection and the Bloomington Drosophila Stock Center for fly strains. We thank Don Gantz at Boston University Medical Center for technical assistance with the electron microscopy. We especially thank Horacio Frydman for providing the image in Figure 1a and helpful comments on the paper. We additionally thank Sharon Gorski and members of the laboratory for helpful discussions. We apologize to authors whose work we are unable to cite due to space limitations. This work was supported by NIH grants to KM (R01 GM60574) and PD (EY016747). ET was supported in part by NICHD training grant 2T 32 HD007387.
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Bass, B., Tanner, E., Mateos San Martín, D. et al. Cell-autonomous requirement for DNaseII in nonapoptotic cell death. Cell Death Differ 16, 1362–1371 (2009). https://doi.org/10.1038/cdd.2009.79
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DOI: https://doi.org/10.1038/cdd.2009.79
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