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PMID: 17982172 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Nucleic acids research ·Vol. 35 ·No. 22 ·2007-00-00 ·Pages 7665-75

Mortusewicz O, Amé JC, Schreiber V, Leonhardt H

Abstract

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.

MeSH Terms
Animals Cell Nucleolus/enzymology Cells, Cultured DNA Damage DNA Repair DNA-Binding Proteins/metabolism Feedback, Physiological Gene Deletion HeLa Cells Humans Kinetics Mice Poly (ADP-Ribose) Polymerase-1 Poly Adenosine Diphosphate Ribose/metabolism Poly(ADP-ribose) Polymerases/chemistry,genetics,metabolism Protein Structure, Tertiary X-ray Repair Cross Complementing Protein 1
Chemicals
DNA-Binding Proteins X-ray Repair Cross Complementing Protein 1 XRCC1 protein, human Xrcc1 protein, mouse Poly Adenosine Diphosphate Ribose PARP1 protein, human PARP2 protein, human Parp1 protein, mouse Poly (ADP-Ribose) Polymerase-1 Poly(ADP-ribose) Polymerases
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Mortusewicz Oliver
Munich Center for Integrated Protein Science CiPS , Ludwig Maximilians University Munich, 82152 Planegg-Martinsried, Germany.
Amé Jean-Christophe
Schreiber Valérie
Leonhardt Heinrich
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Article Info
Journal
Nucleic acids research
Abbr.
Nucleic Acids Res
ISSN
1362-4962
DOI
10.1093/nar/gkm933
Published
2007-00-00
Epub
2007-00-03
Pages
7665-75
Language
English
Region
England
NLM ID
0411011
PMCID
PMC2190722
Subset
IM
External Links
PubMed source DOI: 10.1093/nar/gkm933 PMC Full Text View journal details
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