Phenylbutyrate inhibits homologous recombination induced by camptothecin and methyl methanesulfonate

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 - 2011/8/1

Y1 - 2011/8/1

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

SN - 0027-5107

VL - 713

SP - 64

EP - 75

JO - Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis

JF - Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis

IS - 1-2

ER -