The 89-kDa PARP1 cleavage fragment serves as a cytoplasmic PAR carrier to induce AIF-mediated apoptosis

• Published in: The Journal of biological chemistry Vol. 296; p. 100046
• Main Authors: Mashimo, Masato, Onishi, Mayu, Uno, Arina, Tanimichi, Akari, Nobeyama, Akari, Mori, Mana, Yamada, Sayaka, Negi, Shigeru, Bu, Xiangning, Kato, Jiro, Moss, Joel, Sanada, Noriko, Kizu, Ryoichi, Fujii, Takeshi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2021; American Society for Biochemistry and Molecular Biology
• Subjects: Apoptosis; Apoptosis Inducing Factor - genetics; Apoptosis Inducing Factor - metabolism; apoptosis-inducing factor; Biological Transport, Active; caspase; Caspase 3 - genetics; Caspase 3 - metabolism; Caspase 7 - genetics; Caspase 7 - metabolism; cell death; Cytoplasm - genetics; Cytoplasm - metabolism; HeLa Cells; Humans; parthanatos; Poly (ADP-Ribose) Polymerase-1 - genetics; Poly (ADP-Ribose) Polymerase-1 - metabolism; Poly Adenosine Diphosphate Ribose - genetics; Poly Adenosine Diphosphate Ribose - metabolism; poly(ADP-ribose) polymerase 1; poly(ADP-ribosyl)ation; Proteolysis; PAR; poly(ADP-ribose) polymerase 1; cell death; parthanatos; NLS; poly(ADP-ribosyl)ation; apoptosis; GST; PARP; apoptosis-inducing factor; AIF; caspase
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.RA120.014479

Poly(ADP-ribose) polymerase 1 (PARP1) is a nuclear protein that is activated by binding to DNA lesions and catalyzes poly(ADP-ribosyl)ation of nuclear acceptor proteins, including PARP1 itself, to recruit DNA repair machinery to DNA lesions. When excessive DNA damage occurs, poly(ADP-ribose) (PAR) produced by PARP1 is translocated to the cytoplasm, changing the activity and localization of cytoplasmic proteins, e.g., apoptosis-inducing factor (AIF), hexokinase, and resulting in cell death. This cascade, termed parthanatos, is a caspase-independent programmed cell death distinct from necrosis and apoptosis. In contrast, PARP1 is a substrate of activated caspases 3 and 7 in caspase-dependent apoptosis. Once cleaved, PARP1 loses its activity, thereby suppressing DNA repair. Caspase cleavage of PARP1 occurs within a nuclear localization signal near the DNA-binding domain, resulting in the formation of 24-kDa and 89-kDa fragments. In the present study, we found that caspase activation by staurosporine- and actinomycin D-induced PARP1 autopoly(ADP-ribosyl)ation and fragmentation, generating poly(ADP-ribosyl)ated 89-kDa and 24-kDa PARP1 fragments. The 89-kDa PARP1 fragments with covalently attached PAR polymers were translocated to the cytoplasm, whereas 24-kDa fragments remained associated with DNA lesions. In the cytoplasm, AIF binding to PAR attached to the 89-kDa PARP1 fragment facilitated its translocation to the nucleus. Thus, the 89-kDa PARP1 fragment is a PAR carrier to the cytoplasm, inducing AIF release from mitochondria. Elucidation of the caspase-mediated interaction between apoptosis and parthanatos pathways extend the current knowledge on mechanisms underlying programmed cell death and may lead to new therapeutic targets.