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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 Schuhwerk, Harald Schuhwerk, Harald Bruhn, Christopher Bruhn, Christopher 2017-11-02 eng

Dateiabrufe seit 13.10.2017 (Informationen über die Zugriffsstatistik)

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