Feedback-regulated poly(ADP-ribosyl)ation by PARP-1 is required for rapid response to DNA damage in living cells

Genome integrity is constantly threatened by DNA lesions arising from numerous exogenous and endogenous sources. Survival depends on immediate recognition of these lesions and rapid recruitment of repair factors. Using laser microirradiation and live cell microscopy we found that the DNA-damage depe...

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Bibliographic Details
Published in:Nucleic acids research 2007-12, Vol.35 (22), p.7665-7675
Main Authors: Mortusewicz, Oliver, Amé, Jean-Christophe, Schreiber, Valérie, Leonhardt, Heinrich
Format: Article
Language:English
Subjects:
Animals
Biochemistry, Molecular Biology
Cell Nucleolus - enzymology
Cells, Cultured
DNA Damage
DNA Repair
DNA-Binding Proteins - metabolism
Feedback, Physiological
Gene Deletion
HeLa Cells
Humans
Kinetics
Life Sciences
Mice
Molecular Biology
Poly (ADP-Ribose) Polymerase-1
Poly Adenosine Diphosphate Ribose - metabolism
Poly(ADP-ribose) Polymerases - chemistry
Poly(ADP-ribose) Polymerases - genetics
Poly(ADP-ribose) Polymerases - metabolism
Protein Structure, Tertiary
X-ray Repair Cross Complementing Protein 1
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Summary:Genome integrity is constantly threatened by DNA lesions arising from numerous exogenous and endogenous sources. Survival depends on immediate recognition of these lesions and rapid recruitment of repair factors. Using laser microirradiation and live cell microscopy we found that the DNA-damage dependent poly(ADP-ribose) polymerases (PARP) PARP-1 and PARP-2 are recruited to DNA damage sites, however, with different kinetics and roles. With specific PARP inhibitors and mutations, we could show that the initial recruitment of PARP-1 is mediated by the DNA-binding domain. PARP-1 activation and localized poly(ADP-ribose) synthesis then generates binding sites for a second wave of PARP-1 recruitment and for the rapid accumulation of the loading platform XRCC1 at repair sites. Further PARP-1 poly(ADP-ribosyl)ation eventually initiates the release of PARP-1. We conclude that feedback regulated recruitment of PARP-1 and concomitant local poly(ADP-ribosyl)ation at DNA lesions amplifies a signal for rapid recruitment of repair factors enabling efficient restoration of genome integrity.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkm933