Programmed cell death (or apoptosis) is an evolutionarily conserved, genetically controlled suicide mechanism for cells that, when deregulated, can lead to developmental defects, cancers, and degenerative diseases. In C. elegans, DNA damage induces germ cell death by signaling through
cep-1/p53, ultimately leading to the activation of CED-3/caspase. It has been hypothesized that the major regulatory events controlling cell death occur by cell-autonomous mechanisms, that is, within the dying cell. In support of this, genetic studies in C. elegans have shown that the core apoptosis pathway genes
ced-4/APAF-1 and
ced-3/caspase are required in cells fated to die. However, it is not known whether the upstream signals that activate apoptosis function in a cell-autonomous manner. Here we show that
kri-1, an ortholog of KRIT1/CCM1, which is mutated in the human neurovascular disease cerebral cavernous malformation, is required to activate DNA damage-dependent cell death independently of
cep-1/p53. Interestingly, we find that
kri-1 regulates cell death in a cell-nonautonomous manner, revealing a novel regulatory role for nondying cells in eliciting cell death in response to DNA damage.