Kinetics of poly(ADP-ribosyl)ation, but not PARP1 itself, determines the cell fate in response to DNA damage in vitro and in vivo
| Autor: | Kanstantsin Siniuk, Elena Ferrari, Christopher Bruhn, Harald Schuhwerk, Shamci Monajembashi, Tabea Zubel, Annika Krüger, Zhao-Qi Wang, Torsten Kroll, Paulius Grigaravicius, Wookee Min, Aswin Mangerich, Suheda Erener, Kirstin Kiesow, David Lázaro, Alexander Bürkle, Michael O. Hottiger |
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| Rok vydání: | 2017 |
| Předmět: |
DNA Replication
0301 basic medicine Mice 129 Strain DNA Repair DNA repair DNA damage Poly ADP ribose polymerase Mice Transgenic Genome Integrity Repair and Replication Chromatin remodeling Mice Poly ADP Ribosylation 03 medical and health sciences PARP1 ddc:570 Catalytic Domain Genetics Animals Cells Cultured Polymerase Models Genetic biology DNA replication Mouse Embryonic Stem Cells Base excision repair Molecular biology Kinetics 030104 developmental biology Mutation biology.protein repair and replication Genome integrity Poly(ADP-ribose) Polymerases dna damage kinetics mice parp1 protein DNA Damage |
| Zdroj: | Nucleic Acids Research Nucleic acids research, 45(19):11174-11192 |
| ISSN: | 1362-4962 0305-1048 |
| DOI: | 10.1093/nar/gkx717 |
| Popis: | 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. published |
| Databáze: | OpenAIRE |
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