Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, 76100, Israel.
The Israel Structural Proteomics Center (ISPC), Weizmann Institute of Science, Rehovot, 76100, Israel.
Nat Commun. 2021 Apr 16;12(1):2285. doi: 10.1038/s41467-021-22622-1.
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.
在果蝇胚胎发育过程中，细胞凋亡会消除 30%的原始生殖细胞（PGCs）。抑制细胞凋亡并不会阻止 PGC 的死亡，这表明其与传统的细胞凋亡程序存在差异。在这里，我们证明 PGCs 通常会激活由溶酶体释放的核酸内切酶 II 介导的内在替代性细胞死亡（ACD）途径，导致核转位和随后的 DNA 双链断裂（DSBs）。DSBs 激活 DNA 损伤感应酶聚（ADP-核糖）聚合酶-1（PARP-1）和 DNA 损伤反应的 ATR/Chk1 分支。PARP-1 和核酸内切酶 II 通过 PAR 聚合物从核内释放和核酸内切酶 II 在 AIF 和 CypA 依赖性方式下在核内积累，从而形成正反馈放大环，最终导致 PGC 死亡。鉴于与一种称为 parthanatos 的 ACD 途径的解剖学和分子相似性，这些发现揭示了在果蝇发育过程中活跃的 parthanatos 样细胞死亡途径。
