The 89-kDa PARP1 cleavage fragment serves as a PAR carrier from the nucleus to the cytoplasm to induce parthanatos in caspase-dependent apoptosis

作者：Masato Mashimo, Mayu Onishi, Arina Uno, Akari Tanimichi, Mana Mori, Akari Nobeyama, Sayaka Yamada, Takeshi Fujii · 发表于：Proceedings for Annual Meeting of The Japanese Pharmacological Society · 年份：2018 · DOI：10.1254/jpssuppl.wcp2018.0_po4-11-6 · 研究领域：PARP inhibition in cancer therapy

Parthanatos is a form of programed cell death, which occurs in a PARP1 (PARP) 1-dependent, caspase-independent manner. PARP1 binds DNA-strand breaks via its DNA-binding domain, located near the N-terminus, and then forms poly(ADP-ribose) (PAR) through its catalytic domain, located near the C-terminus; PAR may be attached to the PARP1 automodification domain and nuclear acceptor proteins. Thereafter, some PAR polymers are translocated to the cytoplasm, where they serve as signaling molecules to provide nuclear information to the cytoplasm and mitochondria. After translocation to the cytoplasm, PAR polymers bind to the PAR-binding motif of apoptosis-inducing factor (AIF) and hexokinase 1. PAR promotes the cleavage and release of AIF from mitochondrial membranes. AIF then translocates to the nucleus where it induces DNA fragmentation. In addition, PAR binding to hexokinase 1 inhibits glycolysis, resulting in ATP depletion. A key step in the parthanatos pathway is PAR translocation from the nucleus to the cytoplasm, but its mechanism is unknown.