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Kinetics of poly(ADP-ribosyl)ation, but not PARP1 itself, determines the cell fate in response to DNA damage in vitro and in vivo

Kinetics of poly(ADP-ribosyl)ation, but not PARP1 itself, determines the cell fate in response to DNA damage in vitro and in vivo

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SCHUHWERK, Harald, Christopher BRUHN, Kanstantsin SINIUK, Wookee MIN, Suheda ERENER, Annika KRÜGER, Tabea ZUBEL, Alexander BÜRKLE, Aswin MANGERICH, Zhao-Qi WANG, 2017. Kinetics of poly(ADP-ribosyl)ation, but not PARP1 itself, determines the cell fate in response to DNA damage in vitro and in vivo. In: Nucleic acids research. 45(19), pp. 11174-11192. ISSN 0305-1048. eISSN 1362-4962. Available under: doi: 10.1093/nar/gkx717

@article{Schuhwerk2017-11-02Kinet-40332, title={Kinetics of poly(ADP-ribosyl)ation, but not PARP1 itself, determines the cell fate in response to DNA damage in vitro and in vivo}, year={2017}, doi={10.1093/nar/gkx717}, number={19}, volume={45}, issn={0305-1048}, journal={Nucleic acids research}, pages={11174--11192}, author={Schuhwerk, Harald and Bruhn, Christopher and Siniuk, Kanstantsin and Min, Wookee and Erener, Suheda and Krüger, Annika and Zubel, Tabea and Bürkle, Alexander and Mangerich, Aswin and Wang, Zhao-Qi} }

Erener, Suheda 2017-10-13T12:18:07Z Bürkle, Alexander Mangerich, Aswin Zubel, Tabea Krüger, Annika Erener, Suheda Siniuk, Kanstantsin Krüger, Annika Siniuk, Kanstantsin Mangerich, Aswin Kinetics of poly(ADP-ribosyl)ation, but not PARP1 itself, determines the cell fate in response to DNA damage in vitro and in vivo Min, Wookee Wang, Zhao-Qi Wang, Zhao-Qi 2017-10-13T12:18:07Z One of the fastest cellular responses to genotoxic stress is the formation of poly(ADP-ribose) polymers (PAR) by poly(ADP-ribose)polymerase 1 (PARP1, or ARTD1). PARP1 and its enzymatic product PAR regulate diverse biological processes, such as DNA repair, chromatin remodeling, transcription and cell death. However, the inter-dependent function of the PARP1 protein and its enzymatic activity clouds the mechanism underlying the biological response. We generated a PARP1 knock-in mouse model carrying a point mutation in the catalytic domain of PARP1 (D993A), which impairs the kinetics of the PARP1 activity and the PAR chain complexity in vitro and in vivo, designated as hypo-PARylation. PARP1<sup>D993A/D993A</sup> mice and cells are viable and show no obvious abnormalities. Despite a mild defect in base excision repair (BER), this hypo-PARylation compromises the DNA damage response during DNA replication, leading to cell death or senescence. Strikingly, PARP1<sup>D993A/D993A</sup> mice are hypersensitive to alkylation in vivo, phenocopying the phenotype of PARP1 knockout mice. Our study thus unravels a novel regulatory mechanism, which could not be revealed by classical loss-of-function studies, on how PAR homeostasis, but not the PARP1 protein, protects cells and organisms from acute DNA damage. Min, Wookee Bürkle, Alexander Zubel, Tabea Attribution-NonCommercial 4.0 International Schuhwerk, Harald Schuhwerk, Harald Bruhn, Christopher Bruhn, Christopher 2017-11-02 eng

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