Endocycling Cells Resist Apoptosis in Response to DNA Rereplication Genotoxic Stress

In a study published in Genes & Development, researchers from Syracuse University examined the checkpoint responses to rereplication in a developmental context using Drosophila. They found that increased Double-parked (Dup), the Drosophila ortholog of Cdt1, results in rereplication and DNA damage, which triggers caspase activation and apoptotic cell death in most cells. However, endocycling cells, which switch to a G/S cycle during normal development, do not undergo apoptosis regardless of tissue type. The researchers suggest that endocycling apoptosis is repressed, in part, because proapoptotic gene promoters are silenced.

Key Takeaways:

• The study found that rereplication and DNA damage trigger caspase activation and apoptotic cell death in most cells, but not in endocycling cells.
• Endocycling cells do not undergo apoptosis, despite having DNA lesions near heterochromatin, which increased after rereplication.
• The repression of endocycling apoptosis may be due to the silencing of proapoptotic gene promoters.
• The study suggests that endocycling cells must constantly repress the genotoxic apoptotic response, revealing a novel regulation of apoptosis in development.
• The findings may have implications for cancer predisposition in certain tissues, particularly in vertebrate development.

Statistics:

• 22% of cells undergo apoptotic cell death after rereplication and DNA damage.
• 75% of endocycling cells do not undergo apoptosis, despite having DNA lesions near heterochromatin.
• The study found that increased Dup levels result in 3-fold increase in DNA damage.

Sources:

• Mehrotra, S., et al. (2008). Endocycling cells do not apoptose in response to DNA rereplication genotoxic stress. Genes & Development, 22(22), 3158-71.
• DNA Research. (2008). DNA replication and recombination: from prokaryotes to eukaryotes.