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Published on: February 1, 2018
DNase II mediates a parthanatos-like developmental cell death pathway in Drosophila primordial germ cells
Lama Tarayrah-Ibraheim1, Elital Chass Maurice1, Guy Hadary1
1Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, 76100, Israel.
Abstract:
During Drosophila embryonic development, cell death eliminates 30% of the primordial germ cells (PGCs). Inhibiting apoptosis does not prevent PGC death, suggesting a divergence from the conventional apoptotic program. Here, we demonstrate that PGCs normally activate an intrinsic alternative cell death (ACD) pathway mediated by DNase II release from lysosomes, leading to nuclear translocation and subsequent DNA double-strand breaks (DSBs). DSBs activate the DNA damage-sensing enzyme, Poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) and the ATR/Chk1 branch of the DNA damage response. PARP-1 and DNase II engage in a positive feedback amplification loop mediated by the release of PAR polymers from the nucleus and the nuclear accumulation of DNase II in an AIF- and CypA-dependent manner, ultimately resulting in PGC death. Given the anatomical and molecular similarities with an ACD pathway called parthanatos, these findings reveal a parthanatos-like cell death pathway active during Drosophila development.
Insights
Drosophila primordial germ cells undergo an alternative cell death (ACD) pathway, not apoptosis. This process involves DNase II, DNA breaks, and a feedback loop, revealing a parthanatos-like mechanism during development.
Area of Science:
- Developmental Biology
- Cell Biology
- Genetics
Background:
- Cell death is crucial during Drosophila embryonic development, eliminating ~30% of primordial germ cells (PGCs).
- Inhibition of apoptosis fails to prevent PGC death, indicating a non-apoptotic cell death mechanism.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying PGC death during Drosophila development.
- To investigate the potential divergence from conventional apoptotic pathways.
Main Methods:
- Investigated PGC death pathways using genetic and molecular techniques in Drosophila.
- Analyzed the roles of DNase II, Poly(ADP-ribose) polymerase-1 (PARP-1), and DNA damage response (DDR) pathways.
Main Results:
- PGCs activate an intrinsic alternative cell death (ACD) pathway involving lysosomal DNase II release.
- DNase II triggers nuclear translocation, causing DNA double-strand breaks (DSBs) that activate PARP-1 and the ATR/Chk1 DDR.
- A positive feedback loop between PARP-1 and DNase II, dependent on AIF and CypA, amplifies cell death signaling.
Conclusions:
- Drosophila PGCs undergo a unique ACD pathway mediated by DNase II and PARP-1.
- This pathway shares similarities with parthanatos, suggesting a conserved cell death mechanism across species.
- Identified a novel developmental cell death pathway distinct from canonical apoptosis.
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