The 89-kDa PARP1 cleavage fragment serves as a cytoplasmic PAR carrier to induce AIF-mediated apoptosis
| Autor: | Akari Tanimichi, Jiro Kato, Takeshi Fujii, Arina Uno, Masato Mashimo, Sayaka Yamada, Xiangning Bu, Shigeru Negi, Noriko Sanada, Mana Mori, Joel Moss, Akari Nobeyama, Ryoichi Kizu, Mayu Onishi |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Programmed cell death Cytoplasm Poly Adenosine Diphosphate Ribose PARP poly(ADP-ribose) polymerase DNA damage DNA repair Poly ADP ribose polymerase caspase poly(ADP-ribosyl)ation Poly (ADP-Ribose) Polymerase-1 Biological Transport Active Biochemistry 03 medical and health sciences apoptosis-inducing factor parthanatos GST glutathione-S-transferase Humans Molecular Biology Caspase Caspase 7 030102 biochemistry & molecular biology biology Chemistry Caspase 3 apoptosis Apoptosis Inducing Factor Cell Biology Cell biology AIF apoptosis-inducing factor 030104 developmental biology cell death Apoptosis poly(ADP-ribose) polymerase 1 NLS nuclear localization signal Proteolysis biology.protein Apoptosis-inducing factor PAR poly(ADP-ribose) Research Article HeLa Cells |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X 0021-9258 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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