Phenylbutyrate inhibits homologous recombination induced by camptothecin and methyl methanesulfonate
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Phenylbutyrate inhibits homologous recombination induced by camptothecin and methyl methanesulfonate. / Kaiser, Gitte Schalck; Germann, Susanne Manuela; Westergaard, Tine; Lisby, Michael.
I: Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, Bind 713, Nr. 1-2, 2011, s. 64-75.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Phenylbutyrate inhibits homologous recombination induced by camptothecin and methyl methanesulfonate
AU - Kaiser, Gitte Schalck
AU - Germann, Susanne Manuela
AU - Westergaard, Tine
AU - Lisby, Michael
N1 - 2011 Elsevier B.V. All rights reserved.
PY - 2011
Y1 - 2011
N2 - Homologous recombination is accompanied by extensive changes to chromatin organization at the site of DNA damage. Some of these changes are mediated through acetylation/deacetylation of histones. Here, we show that recombinational repair of DNA damage induced by the anti-cancer drug camptothecin (CPT) and the alkylating agent methyl methanesulfonate (MMS) is blocked by sodium phenylbutyrate (PBA) in the budding yeast Saccharomyces cerevisiae. In particular, PBA suppresses CPT- and MMS-induced genetic recombination as well as DNA double-strand break repair during mating-type interconversion. Treatment with PBA is accompanied by a dramatic reduction in histone H4 lysine 8 acetylation. Live cell imaging of homologous recombination proteins indicates that repair of CPT-induced DNA damage is redirected to a non-recombinogenic pathway in the presence of PBA without loss in cell viability. In contrast, the suppression of MMS-induced recombination by PBA is accompanied by a dramatic loss in cell viability. Taken together, our results demonstrate that PBA inhibits DNA damage-induced homologous recombination likely by mediating changes in chromatin acetylation. Moreover, the combination of PBA with genotoxic agents can lead to different cell fates depending on the type of DNA damage inflicted.
AB - Homologous recombination is accompanied by extensive changes to chromatin organization at the site of DNA damage. Some of these changes are mediated through acetylation/deacetylation of histones. Here, we show that recombinational repair of DNA damage induced by the anti-cancer drug camptothecin (CPT) and the alkylating agent methyl methanesulfonate (MMS) is blocked by sodium phenylbutyrate (PBA) in the budding yeast Saccharomyces cerevisiae. In particular, PBA suppresses CPT- and MMS-induced genetic recombination as well as DNA double-strand break repair during mating-type interconversion. Treatment with PBA is accompanied by a dramatic reduction in histone H4 lysine 8 acetylation. Live cell imaging of homologous recombination proteins indicates that repair of CPT-induced DNA damage is redirected to a non-recombinogenic pathway in the presence of PBA without loss in cell viability. In contrast, the suppression of MMS-induced recombination by PBA is accompanied by a dramatic loss in cell viability. Taken together, our results demonstrate that PBA inhibits DNA damage-induced homologous recombination likely by mediating changes in chromatin acetylation. Moreover, the combination of PBA with genotoxic agents can lead to different cell fates depending on the type of DNA damage inflicted.
KW - Alkylating Agents
KW - Antineoplastic Agents, Phytogenic
KW - Camptothecin
KW - DNA Repair
KW - Genes, Mating Type, Fungal
KW - Humans
KW - Methyl Methanesulfonate
KW - Phenylbutyrates
KW - Rad52 DNA Repair and Recombination Protein
KW - Recombination, Genetic
KW - Saccharomyces cerevisiae
U2 - 10.1016/j.mrfmmm.2011.05.016
DO - 10.1016/j.mrfmmm.2011.05.016
M3 - Journal article
C2 - 21658395
VL - 713
SP - 64
EP - 75
JO - Mutation Research Letters
JF - Mutation Research Letters
SN - 0027-5107
IS - 1-2
ER -
ID: 38060721