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Published on: November 29, 2016
Cell-nonautonomous regulation of C. elegans germ cell death by kri-1
Shu Ito1, Sebastian Greiss, Anton Gartner
1Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
Abstract:
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.
Insights
DNA damage triggers programmed cell death (apoptosis) through cell-nonautonomous signaling. The KRI-1 protein regulates this process, revealing a novel role for non-dying cells in apoptosis.
Area of Science:
- Cell Biology
- Genetics
- Developmental Biology
Background:
- Programmed cell death (apoptosis) is a vital cellular process implicated in development, cancer, and disease.
- In C. elegans, DNA damage induces germ cell death via cep-1/p53 and CED-3/caspase.
- Apoptosis regulation was thought to be primarily cell-autonomous, occurring within the dying cell.
Purpose of the Study:
- To investigate the mechanism of upstream signal activation in DNA damage-induced apoptosis.
- To determine if apoptosis-activating signals function in a cell-autonomous or cell-nonautonomous manner.
- To explore the role of KRI-1 in DNA damage response and cell death.
Main Methods:
- Genetic analysis in C. elegans.
- Investigating the function of kri-1, an ortholog of human KRIT1/CCM1.
- Assessing DNA damage-induced germ cell death pathways.
Main Results:
- KRI-1 is essential for activating DNA damage-dependent cell death, independent of cep-1/p53.
- KRI-1 functions in a cell-nonautonomous manner to regulate apoptosis.
- This identifies a novel role for non-dying cells in initiating apoptosis in response to DNA damage.
Conclusions:
- The KRI-1 protein mediates cell-nonautonomous regulation of DNA damage-induced apoptosis.
- This finding challenges the paradigm of purely cell-autonomous control of apoptosis.
- Nondying cells play a crucial role in orchestrating cell death in response to genotoxic stress.
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