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DNase II Mediates A Parthanatos-like Developmental Cell Death Pathway In Drosophila Primordial Germ Cells

Lama Tarayrah-Ibraheim, Elital Chass Maurice, Guy Hadary, Sharon Ben-Hur, Alina Kolpakova, Tslil Braun, Yoav Peleg, Keren Yacobi-Sharon, Eli Arama

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AbstractDuringDrosophilaembryonic 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 duringDrosophiladevelopment.