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  • Review Article
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Trashing the genome: the role of nucleases during apoptosis

Nature Reviews Molecular Cell Biology volume 6, pages 677–688 (2005)Cite this article

Key Points

  • DNA degradation during apoptosis can be divided into two stages. First, DNA is digested by nucleases that are provided by the apoptotic cell itself (cell-autonomous nucleases). Post-engulfment, DNA is further digested by lysosomal enzymes that are provided by the phagocytic cells (waste-management nucleases).

  • Cell-autonomous DNA cleavage is not essential for individual organisms but might affect the progression of apoptosis. By contrast, engulfment-mediated DNA cleavage is necessary for the life of the organism.

  • The role of DNA degradation during apoptosis might have originally been to enable the clearance of harmful DNA (viral or other pathogenic DNA) and for the prevention of self-immunization. DNA degradation also facilitates both killing and engulfment during the apoptotic process.

  • Apoptotic DNA degradation is surprisingly complex, and is carried out by several nucleases. CAD (caspase-activated DNase) and DNase II are particularly important, but other nucleases could have important roles, depending on the apoptotic stimuli and cell types.

  • Low molecular weight (LMW) DNA cleavage is a characteristic of apoptosis but is not essential for cell death. Little is known about the high molecular weight (HMW) DNA cleavage that precedes LMW DNA cleavage. It might be important for nuclear apoptosis.

Abstract

Two classes of nucleases degrade the cellular DNA during apoptosis. Cell-autonomous nucleases cleave DNA within the dying cell. They are not essential for apoptotic cell death or the life of the organism, but they might affect the efficiency of the process. By contrast, waste-management nucleases are essential for the life of the organism. In post-engulfment DNA degradation, the DNA of apoptotic cells is destroyed in lysosomes of the cells that have phagocytosed the corpses. Waste-management nucleases also destroy DNA that is released into the extracellular compartment. Here, we describe the complex group of nucleases that are involved in DNA destruction during apoptotic cell death.

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Figure 1: Coordinated chromatin condensation and cleavage of the DNA in apoptosis.
Figure 2: HMW and LMW cleavage in apoptosis.
Figure 3: Use of TUNEL to detect cell death in human tissue.
Figure 4: Cell-autonomous and waste-management nucleases in apoptosis and necrosis.
Figure 5: Introduction to the CAD nuclease.
Figure 6: The pathways of DNA processing in apoptosis and necrosis.
Figure 7: The pathway of DNA degradation during cell death in Caenorhabditis elegans.

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Acknowledgements

Work in the Earnshaw laboratory is supported by the National Institutes of Health and The Wellcome Trust. W.E. is a Wellcome Trust Principle Research Fellow.

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  1. Wellcome Trust Centre for Cell Biology, Institute of Cell Biology, University of Edinburgh, Swann Building, King's Buildings, Mayfield Road, EH9 3JR, Edinburgh, UK

    Kumiko Samejima & William C. Earnshaw

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  1. Kumiko Samejima
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Correspondence to William C. Earnshaw.

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DATABASES

Swiss-Prot

CAD

ICAD

NUC-1

FURTHER INFORMATION

William Earnshaw's laboratory

Glossary

TUNEL

(terminal deoxynucleotidyl transferase dUTP-mediated nick end labelling). The most commonly used technique to detect apoptotic cells, which labels DNA breaks with 3′-OH ends.

CELL-AUTONOMOUS NUCLEASE

A nuclease that functions in the dying cell to degrade its DNA.

WASTE-MANAGEMENT NUCLEASE

A nuclease that functions either in cells that ingest apoptotic corpses, or as a secreted enzyme in the extracellular environment to degrade DNA released as a consequence of cell death.

NECROSIS

Accidental cell death due to the loss of cellular homeostasis, which occurs following injury, radiation or treatment with chemicals, and is accompanied by an inflammatory response.

HIGH-MOBILITY GROUP PROTEINS

(HMGs). Abundant chromosomal proteins that facilitate the assembly of higher-order structures. One HMG protein, HMG1, leaks out from necrotic cells (but not apoptotic cells) and induces inflammation.

PEPTIDYLPROLYL CIS–TRANS-ISOMERASE

An enzymes that facilitates the cis-trans interconversion of the peptidyl–prolyl bond during protein folding.

EXOSOME

A protein complex that comprises 3′→5′ exonucleases (11 in Saccharomyces cerevisiae) that are involved in the processing and degradation of RNA.

3′→5′ EXONUCLEASE

A nuclease that degrades DNA or RNA from an available end in the 3′ to 5′ direction.

FLAVOPROTEIN

An enzyme that contains a chemically linked FAD moiety, and that is active in the oxidation of other molecules in animal cells.

OXIDOREDUCTASE

A class of enzyme that either oxidizes or reduces substrates using either FAD or NAD as a cofactor.

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Samejima, K., Earnshaw, W. Trashing the genome: the role of nucleases during apoptosis. Nat Rev Mol Cell Biol 6, 677–688 (2005). https://doi.org/10.1038/nrm1715

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