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Inhibition of poly (ADP-ribose) polymerase activates ATM which is required for subsequent homologous recombination repair

Poly (ADP-ribose) polymerase (PARP-1), ATM and DNA-dependent protein kinase (DNA-PK) are all involved in responding to DNA damage to activate pathways responsible for cellular survival. Here, we demonstrate that PARP-1(−/−) cells are sensitive to the ATM inhibitor KU55933 and conversely that AT cell...

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Detalles Bibliográficos
Autores principales: Bryant, Helen E., Helleday, Thomas
Formato: Texto
Lenguaje:English
Publicado: Oxford University Press 2006
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1410911/
https://www.ncbi.nlm.nih.gov/pubmed/16556909
http://dx.doi.org/10.1093/nar/gkl108
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author Bryant, Helen E.
Helleday, Thomas
author_facet Bryant, Helen E.
Helleday, Thomas
author_sort Bryant, Helen E.
collection PubMed
description Poly (ADP-ribose) polymerase (PARP-1), ATM and DNA-dependent protein kinase (DNA-PK) are all involved in responding to DNA damage to activate pathways responsible for cellular survival. Here, we demonstrate that PARP-1(−/−) cells are sensitive to the ATM inhibitor KU55933 and conversely that AT cells are sensitive to the PARP inhibitor 4-amino-1,8-napthalamide. In addition, PARP-1(−/−) cells are shown to be sensitive to the DNA-PK inhibitor NU7026 and DNA-PKcs or Ku80 defective cells shown to be sensitive to PARP inhibitors. We believe PARP inhibition results in an increase in unresolved spontaneous DNA single-strand breaks (SSBs), which collapse replication forks and trigger homologous recombination repair (HRR). We show that ATM is activated following inhibition of PARP. Furthermore, PARP inhibitor-induced HRR is abolished in ATM, but not DNA-PK, inhibited cells. ATM and DNA-PK inhibition together give the same sensitivity to PARP inhibitors as ATM alone, indicating that ATM functions in the same pathways as DNA-PK for survival at collapsed forks, likely in non-homologous end joining (NHEJ). Altogether, we suggest that ATM is activated by PARP inhibitor-induced collapsed replication forks and may function upstream of HRR in the repair of certain types of double-strand breaks (DSBs).
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spelling pubmed-14109112006-03-28 Inhibition of poly (ADP-ribose) polymerase activates ATM which is required for subsequent homologous recombination repair Bryant, Helen E. Helleday, Thomas Nucleic Acids Res Article Poly (ADP-ribose) polymerase (PARP-1), ATM and DNA-dependent protein kinase (DNA-PK) are all involved in responding to DNA damage to activate pathways responsible for cellular survival. Here, we demonstrate that PARP-1(−/−) cells are sensitive to the ATM inhibitor KU55933 and conversely that AT cells are sensitive to the PARP inhibitor 4-amino-1,8-napthalamide. In addition, PARP-1(−/−) cells are shown to be sensitive to the DNA-PK inhibitor NU7026 and DNA-PKcs or Ku80 defective cells shown to be sensitive to PARP inhibitors. We believe PARP inhibition results in an increase in unresolved spontaneous DNA single-strand breaks (SSBs), which collapse replication forks and trigger homologous recombination repair (HRR). We show that ATM is activated following inhibition of PARP. Furthermore, PARP inhibitor-induced HRR is abolished in ATM, but not DNA-PK, inhibited cells. ATM and DNA-PK inhibition together give the same sensitivity to PARP inhibitors as ATM alone, indicating that ATM functions in the same pathways as DNA-PK for survival at collapsed forks, likely in non-homologous end joining (NHEJ). Altogether, we suggest that ATM is activated by PARP inhibitor-induced collapsed replication forks and may function upstream of HRR in the repair of certain types of double-strand breaks (DSBs). Oxford University Press 2006 2006-03-23 /pmc/articles/PMC1410911/ /pubmed/16556909 http://dx.doi.org/10.1093/nar/gkl108 Text en © The Author 2006. Published by Oxford University Press. All rights reserved
spellingShingle Article
Bryant, Helen E.
Helleday, Thomas
Inhibition of poly (ADP-ribose) polymerase activates ATM which is required for subsequent homologous recombination repair
title Inhibition of poly (ADP-ribose) polymerase activates ATM which is required for subsequent homologous recombination repair
title_full Inhibition of poly (ADP-ribose) polymerase activates ATM which is required for subsequent homologous recombination repair
title_fullStr Inhibition of poly (ADP-ribose) polymerase activates ATM which is required for subsequent homologous recombination repair
title_full_unstemmed Inhibition of poly (ADP-ribose) polymerase activates ATM which is required for subsequent homologous recombination repair
title_short Inhibition of poly (ADP-ribose) polymerase activates ATM which is required for subsequent homologous recombination repair
title_sort inhibition of poly (adp-ribose) polymerase activates atm which is required for subsequent homologous recombination repair
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1410911/
https://www.ncbi.nlm.nih.gov/pubmed/16556909
http://dx.doi.org/10.1093/nar/gkl108
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