Abstract
The present paper proposes a new level of regulation of programmed cell death (PCD) in developing systems based on epigenetics. We argue against the traditional view of PCD as an altruistic “cell suicide” activated by specific gene-encoded signals with the function of favoring the development of their neighboring progenitors to properly form embryonic organs. In contrast, we propose that signals and local tissue interactions responsible for growth and differentiation of the embryonic tissues generate domains where cells retain an epigenetic profile sensitive to DNA damage that results in its subsequent elimination in a fashion reminiscent of what happens with scaffolding at the end of the construction of a building. Canonical death genes, including Bcl-2 family members, caspases, and lysosomal proteases, would reflect the downstream molecular machinery that executes the dying process rather than being master cell death regulatory signals.
Highlights
The present paper proposes a new level of regulation of programmed cell death (PCD) in developing systems based on epigenetics
Among the morpho-structural features that differentiate apoptosis from necrosis, the following can be highlighted: apoptotic cells appear rounded, they preserve the integrity of the membranes, and in the nucleus the chromatin appears densified with clumps of greater density in their contour
Apoptosis was thought to be an active genetically programmed degeneration involving the activation of endogenous endonucleases [8], while necrosis, was considered a passive process resulting from circumstances outside the cell
Summary
The hypothesis of a genetic regulation of developmental cell death became intensely reinforced by the identification of a number of genes in the nematode Caernohabditis elegans (C. elegans), termed “cell death abnormal genes” (Ced genes) whose mutation abolished the physiological dying process occurring in the course of development of this worm [5]. Bcl-2 was the first gene associated with cell death in mammalian cells, but soon a complex regulatory network constituted by a large family of proteins sharing one or various characteristic domains of BCL-2, termed BH domains (BCL-2 homology domains), was discovered. Another C. elegans cell death abnormality gene, Ced-3, which is crucial for the execution of cell death in the worm and is found downstream of Ced-9 in the death cascade [13], was found to be homologous to a family of cysteine-aspartic proteases, called caspases, which orchestrate most of the steps of the apoptotic process in vertebrate organisms. The functions of executioner caspases include the cleavage of distinct structural and regulatory proteins and the activation of caspase-dependent endonuclease that in turn break the DNA at the internucleosomal spaces [8]
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