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Poly(ADP-ribose) Polymerase 1 Mediates Rab5 Inactivation after DNA Damage
Masato Mashimo1, Akane Morozumi1, Akari Nobeyama1
1Laboratory of Pharmacology, Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kyotanabe 610-0395, Kyoto, Japan.
International Journal of Molecular Sciences
|July 27, 2022
Summary
DNA damage triggers programmed cell death (parthanatos) by inhibiting nutrient uptake. Poly(ADP-ribose) polymerase 1 (PARP1) activation leads to Rab5 inactivation, blocking endocytosis and causing cell death.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- Parthanatos is a programmed cell death pathway initiated by DNA damage.
- Poly(ADP-ribose) polymerase 1 (PARP1) mediates parthanatos by synthesizing poly(ADP-ribose) (PAR) chains.
- PAR translocation to the cytoplasm affects protein function, leading to cell death.
Purpose of the Study:
- To investigate the role of endocytosis in parthanatos.
- To identify the molecular mechanisms linking PARP1 activation to cellular dysfunction after DNA damage.
Main Methods:
- Proteomic analysis to identify PAR-binding proteins.
- Cellular assays to assess endocytosis and nutrient uptake.
- Biochemical experiments to study Rab5 activity and its interaction with PAR.
Main Results:
- Proteomic studies indicated that endocytic proteins bind PAR after PARP1 activation.
- PARP1-generated PAR was found to bind and suppress the activity of Rab5, a key regulator of endocytosis.
- Rab5 dissociation from endosomal vesicles inhibited the uptake of membrane-impermeant nutrients.
Conclusions:
- PARP1-mediated inhibition of Rab5 activity and subsequent nutrient uptake represents a novel pathway in parthanatos.
- This mechanism contributes to cell starvation and death following DNA damage.
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