ATR-p53 restricts homologous recombination in response to replicative stress but does not limit DNA interstrand crosslink repair in lung cancer cells.
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ATR-p53 restricts homologous recombination in response to replicative stress but does not limit DNA interstrand crosslink repair in lung cancer cells. / Sirbu, Bianca M; Lachmayer, Sarah J.; Wülfing, Verena; Marten, Lara M.; Clarkson, Katie E; Lee, Linda W; Gheorghiu, Liliana; Zou, Lee; Powell, Simon N; Dahm-Daphi, Jochen; Willers, Henning.
In: PLOS ONE, Vol. 6, No. 8, 8, 2011, p. 23053.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - ATR-p53 restricts homologous recombination in response to replicative stress but does not limit DNA interstrand crosslink repair in lung cancer cells.
AU - Sirbu, Bianca M
AU - Lachmayer, Sarah J.
AU - Wülfing, Verena
AU - Marten, Lara M.
AU - Clarkson, Katie E
AU - Lee, Linda W
AU - Gheorghiu, Liliana
AU - Zou, Lee
AU - Powell, Simon N
AU - Dahm-Daphi, Jochen
AU - Willers, Henning
PY - 2011
Y1 - 2011
N2 - Homologous recombination (HR) is required for the restart of collapsed DNA replication forks and error-free repair of DNA double-strand breaks (DSB). However, unscheduled or hyperactive HR may lead to genomic instability and promote cancer development. The cellular factors that restrict HR processes in mammalian cells are only beginning to be elucidated. The tumor suppressor p53 has been implicated in the suppression of HR though it has remained unclear why p53, as the guardian of the genome, would impair an error-free repair process. Here, we show for the first time that p53 downregulates foci formation of the RAD51 recombinase in response to replicative stress in H1299 lung cancer cells in a manner that is independent of its role as a transcription factor. We find that this downregulation of HR is not only completely dependent on the binding site of p53 with replication protein A but also the ATR/ATM serine 15 phosphorylation site. Genetic analysis suggests that ATR but not ATM kinase modulates p53's function in HR. The suppression of HR by p53 can be bypassed under experimental conditions that cause DSB either directly or indirectly, in line with p53's role as a guardian of the genome. As a result, transactivation-inactive p53 does not compromise the resistance of H1299 cells to the interstrand crosslinking agent mitomycin C. Altogether, our data support a model in which p53 plays an anti-recombinogenic role in the ATR-dependent mammalian replication checkpoint but does not impair a cell's ability to use HR for the removal of DSB induced by cytotoxic agents.
AB - Homologous recombination (HR) is required for the restart of collapsed DNA replication forks and error-free repair of DNA double-strand breaks (DSB). However, unscheduled or hyperactive HR may lead to genomic instability and promote cancer development. The cellular factors that restrict HR processes in mammalian cells are only beginning to be elucidated. The tumor suppressor p53 has been implicated in the suppression of HR though it has remained unclear why p53, as the guardian of the genome, would impair an error-free repair process. Here, we show for the first time that p53 downregulates foci formation of the RAD51 recombinase in response to replicative stress in H1299 lung cancer cells in a manner that is independent of its role as a transcription factor. We find that this downregulation of HR is not only completely dependent on the binding site of p53 with replication protein A but also the ATR/ATM serine 15 phosphorylation site. Genetic analysis suggests that ATR but not ATM kinase modulates p53's function in HR. The suppression of HR by p53 can be bypassed under experimental conditions that cause DSB either directly or indirectly, in line with p53's role as a guardian of the genome. As a result, transactivation-inactive p53 does not compromise the resistance of H1299 cells to the interstrand crosslinking agent mitomycin C. Altogether, our data support a model in which p53 plays an anti-recombinogenic role in the ATR-dependent mammalian replication checkpoint but does not impair a cell's ability to use HR for the removal of DSB induced by cytotoxic agents.
KW - Animals
KW - Humans
KW - Cells, Cultured
KW - Mice
KW - Mutation
KW - Cell Line, Tumor
KW - Flow Cytometry
KW - RNA Interference
KW - Cell Survival/drug effects
KW - Tumor Suppressor Protein p53/genetics/metabolism
KW - DNA Damage
KW - Protein-Serine-Threonine Kinases/genetics/metabolism
KW - Homologous Recombination
KW - DNA Breaks, Double-Stranded/drug effects
KW - Cell Cycle Proteins/genetics/metabolism
KW - Cross-Linking Reagents/pharmacology
KW - DNA Repair
KW - DNA Replication/drug effects
KW - Lung Neoplasms/genetics/metabolism/pathology
KW - Mitomycin/pharmacology
KW - Rad51 Recombinase/genetics/metabolism
KW - Thymidine/pharmacology
KW - Transcriptional Activation/genetics
KW - Animals
KW - Humans
KW - Cells, Cultured
KW - Mice
KW - Mutation
KW - Cell Line, Tumor
KW - Flow Cytometry
KW - RNA Interference
KW - Cell Survival/drug effects
KW - Tumor Suppressor Protein p53/genetics/metabolism
KW - DNA Damage
KW - Protein-Serine-Threonine Kinases/genetics/metabolism
KW - Homologous Recombination
KW - DNA Breaks, Double-Stranded/drug effects
KW - Cell Cycle Proteins/genetics/metabolism
KW - Cross-Linking Reagents/pharmacology
KW - DNA Repair
KW - DNA Replication/drug effects
KW - Lung Neoplasms/genetics/metabolism/pathology
KW - Mitomycin/pharmacology
KW - Rad51 Recombinase/genetics/metabolism
KW - Thymidine/pharmacology
KW - Transcriptional Activation/genetics
U2 - 10.1371/journal.pone.0023053
DO - 10.1371/journal.pone.0023053
M3 - SCORING: Journal article
VL - 6
SP - 23053
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 8
M1 - 8
ER -
