Type of Publication: | Journal article |
Publication status: | Published |
URI (citable link): | http://nbn-resolving.de/urn:nbn:de:bsz:352-2--1bx5fndcdzjn97 |
Author: | Schuhwerk, Harald; Bruhn, Christopher; Siniuk, Kanstantsin; Min, Wookee; Erener, Suheda; Krüger, Annika; Zubel, Tabea; Bürkle, Alexander; Mangerich, Aswin; Wang, Zhao-Qi et al. |
Year of publication: | 2017 |
Published in: | Nucleic acids research ; 45 (2017), 19. - pp. 11174-11192. - ISSN 0305-1048. - eISSN 1362-4962 |
Pubmed ID: | 28977496 |
DOI (citable link): | https://dx.doi.org/10.1093/nar/gkx717 |
Summary: |
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. PARP1D993A/D993A 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, PARP1D993A/D993A 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.
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Subject (DDC): | 570 Biosciences, Biology |
Keywords: | dna damage, kinetics, mice, parp1 protein |
Link to License: | Attribution-NonCommercial 4.0 International |
Bibliography of Konstanz: | Yes |
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} }
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