Researchers at the Weizmann Institute identified two epithelial cell types—DARE and NARE—that survive despite activating the initiator caspase Dronc, then drive tissue regeneration after ionizing radiation. Using a caspase-activity sensor in fruit fly larvae, they found that a membrane-associated protein tethers Dronc and prevents effector caspase activation; disabling this protein reduces survival and regrowth. The DARE–NARE interplay mediates compensatory proliferation, a process that aids repair but may also underlie some tumors’ resistance to radiotherapy.
Some Cells Turn On Death Signals — And Still Survive: The Discovery of DARE and NARE Cells
Scientists Discovered How Our Cells Can Defy Deathspanteldotru - Getty Images
Most cells instructed to die follow a tidy program: they activate specialized enzymes that dismantle proteins and allow components to be recycled. But new research shows a surprising exception. Some cells switch on death signals and initiator enzymes yet avoid execution, survive severe damage such as ionizing radiation, and even help rebuild tissue.
How apoptosis normally works. Apoptosis, or programmed cell death, is driven by proteases called caspases. Initiator caspases sense severe damage and then activate effector caspases, which cleave structural and regulatory proteins so the cell can be removed without harming its neighbors. In healthy tissue, caspase activity is held in check by inhibitor proteins; when a cell must be removed, the Reaper family of proteins releases that inhibition and apoptosis proceeds.
But caspase activation isn’t always a one-way ticket to death. For decades, researchers have observed cells that begin apoptotic signaling yet survive and adopt a resilient, regenerative state—sometimes described as “zombie” behavior. Until now, the mechanisms behind that survival were poorly understood.
New findings from the Weizmann Institute. A team led by Eli Arama and Tslil Braun at the Weizmann Institute of Science used an improved caspase-activity sensor to study fruit fly (Drosophila melanogaster) larvae exposed to high doses of ionizing radiation. Their study, published in Nature Communications, identifies two distinct epithelial cell populations that resist apoptosis after radiation: Dronc-activating radiation-induced apoptosis-resistant epithelial (DARE) cells and non-Dronc-activating radiation-induced apoptosis-resistant epithelial (NARE) cells.
What they found
Among the seven fruit-fly caspases, the initiator Dronc triggers the pathway while effector caspases such as Drice and Dcp-1 normally finish the job after activation by the adaptor protein Dark. In DARE and NARE cells the Dronc initiation signal is present, but downstream effector caspases do not execute cell demolition. The researchers showed that Dronc activity in DARE cells promotes regeneration both cell-autonomously (within the cells themselves) and non-cell-autonomously (in neighboring tissue), and that this effect occurs independently of the Dark adaptor and the effector caspases.
Mechanistically, the team proposes that a membrane-associated protein sequesters (tethers) Dronc at the cell membrane, preventing it from activating effector caspases. When the membrane-sequestering protein was disabled experimentally, DARE cells underwent apoptosis and tissue regeneration was markedly reduced—demonstrating the protein’s protective role.
Cooperation and consequences
DARE and NARE cells are interdependent: DARE cells secrete growth-promoting signals that empower nearby NARE cells, while signals from NARE cells help restrain unchecked DARE proliferation. Together they mediate compensatory proliferation—surviving apoptosis-resistant cells multiply and replace damaged tissue, sometimes restoring nearly half of the lost mass after irradiation.
Clinical implications. While this escape from death aids normal tissue repair, the same mechanism can be harmful in cancer. Preventing cell death can allow malignant cells to survive radiotherapy, contributing to treatment resistance and recurrence. Because many anticancer therapies and roughly two-thirds of cancer patients rely on radiation-induced apoptosis, understanding how cells resist this fate is critical to improving treatment strategies.
"Given that most current anticancer therapies…induce apoptotic cell death, and that approximately two-thirds of cancer patients receive radiotherapy, understanding how certain cells resist radiation-induced apoptosis and subsequently proliferate is critical," the authors write, noting that these insights could guide development of more targeted, effective therapies.
What’s next? The discovery in fruit flies provides a molecular framework to search for similar cells and mechanisms in mammals. If comparable pathways operate in human tissues or tumors, targeting the membrane-sequestering interaction or the signaling between DARE- and NARE-like cells could help overcome resistance to radiotherapy and reduce recurrence.
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