Hyperactivation of PARP triggers nonhomologous end-joining in repair-deficient mouse fibroblasts.
Regulation of poly(ADP-ribose) (PAR) synthesis and turnover is critical to determining cell fate after genotoxic stress. Hyperactivation of PAR synthesis by poly(ADP-ribose) polymerase-1 (PARP-1) occurs when cells deficient in DNA repair are exposed to genotoxic agents; however, the function of this...
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2012-01-01
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doaj-5097241639b2458cb11e13c5211c71e82020-11-24T20:50:00ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-01711e4930110.1371/journal.pone.0049301Hyperactivation of PARP triggers nonhomologous end-joining in repair-deficient mouse fibroblasts.Natalie R GassmanDonna F StefanickPadmini S KedarJulie K HortonSamuel H WilsonRegulation of poly(ADP-ribose) (PAR) synthesis and turnover is critical to determining cell fate after genotoxic stress. Hyperactivation of PAR synthesis by poly(ADP-ribose) polymerase-1 (PARP-1) occurs when cells deficient in DNA repair are exposed to genotoxic agents; however, the function of this hyperactivation has not been adequately explained. Here, we examine PAR synthesis in mouse fibroblasts deficient in the base excision repair enzyme DNA polymerase β (pol β). The extent and duration of PARP-1 activation was measured after exposure to either the DNA alkylating agent, methyl methanesulfonate (MMS), or to low energy laser-induced DNA damage. There was strong DNA damage-induced hyperactivation of PARP-1 in pol β nullcells, but not in wild-type cells. In the case of MMS treatment, PAR synthesis did not lead to cell death in the pol β null cells, but instead resulted in increased PARylation of the nonhomologous end-joining (NHEJ) protein Ku70 and increased association of Ku70 with PARP-1. Inhibition of the NHEJ factor DNA-PK, under conditions of MMS-induced PARP-1 hyperactivation, enhanced necrotic cell death. These data suggest that PARP-1 hyperactivation is a protective mechanism triggering the classical-NHEJ DNA repair pathway when the primary alkylated base damage repair pathway is compromised.http://europepmc.org/articles/PMC3492265?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Natalie R Gassman Donna F Stefanick Padmini S Kedar Julie K Horton Samuel H Wilson |
spellingShingle |
Natalie R Gassman Donna F Stefanick Padmini S Kedar Julie K Horton Samuel H Wilson Hyperactivation of PARP triggers nonhomologous end-joining in repair-deficient mouse fibroblasts. PLoS ONE |
author_facet |
Natalie R Gassman Donna F Stefanick Padmini S Kedar Julie K Horton Samuel H Wilson |
author_sort |
Natalie R Gassman |
title |
Hyperactivation of PARP triggers nonhomologous end-joining in repair-deficient mouse fibroblasts. |
title_short |
Hyperactivation of PARP triggers nonhomologous end-joining in repair-deficient mouse fibroblasts. |
title_full |
Hyperactivation of PARP triggers nonhomologous end-joining in repair-deficient mouse fibroblasts. |
title_fullStr |
Hyperactivation of PARP triggers nonhomologous end-joining in repair-deficient mouse fibroblasts. |
title_full_unstemmed |
Hyperactivation of PARP triggers nonhomologous end-joining in repair-deficient mouse fibroblasts. |
title_sort |
hyperactivation of parp triggers nonhomologous end-joining in repair-deficient mouse fibroblasts. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2012-01-01 |
description |
Regulation of poly(ADP-ribose) (PAR) synthesis and turnover is critical to determining cell fate after genotoxic stress. Hyperactivation of PAR synthesis by poly(ADP-ribose) polymerase-1 (PARP-1) occurs when cells deficient in DNA repair are exposed to genotoxic agents; however, the function of this hyperactivation has not been adequately explained. Here, we examine PAR synthesis in mouse fibroblasts deficient in the base excision repair enzyme DNA polymerase β (pol β). The extent and duration of PARP-1 activation was measured after exposure to either the DNA alkylating agent, methyl methanesulfonate (MMS), or to low energy laser-induced DNA damage. There was strong DNA damage-induced hyperactivation of PARP-1 in pol β nullcells, but not in wild-type cells. In the case of MMS treatment, PAR synthesis did not lead to cell death in the pol β null cells, but instead resulted in increased PARylation of the nonhomologous end-joining (NHEJ) protein Ku70 and increased association of Ku70 with PARP-1. Inhibition of the NHEJ factor DNA-PK, under conditions of MMS-induced PARP-1 hyperactivation, enhanced necrotic cell death. These data suggest that PARP-1 hyperactivation is a protective mechanism triggering the classical-NHEJ DNA repair pathway when the primary alkylated base damage repair pathway is compromised. |
url |
http://europepmc.org/articles/PMC3492265?pdf=render |
work_keys_str_mv |
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