title: Cyclo(phenylalanine-proline) induces DNA damage in mammalian cells via reactive oxygen species.
abstract: Cyclo(phenylalanine-proline) is produced by various organisms such as animals, plants, bacteria and fungi. It has diverse biological functions including anti-fungal activity, anti-bacterial activity and molecular signalling. However, a few studies have demonstrated the effect of cyclo(phenylalanine-proline) on the mammalian cellular processes, such as cell growth and apoptosis. In this study, we investigated whether cyclo(phenylalanine-proline) affects cellular responses associated with DNA damage in mammalian cells. We found that treatment of 1 mM cyclo(phenylalanine-proline) induces phosphorylation of H2AX (S139) through ATM-CHK2 activation as well as DNA double strand breaks. Gene expression analysis revealed that a subset of genes related to regulation of reactive oxygen species (ROS) scavenging and production is suppressed by the cyclo(phenylalanine-proline) treatment. We also found that cyclo(phenylalanine-proline) treatment induces perturbation of the mitochondrial membrane, resulting in increased ROS, especially superoxide, production. Collectively, our study suggests that cyclo(phenylalanine-proline) treatment induces DNA damage via elevation of ROS in mammalian cells. Our findings may help explain the mechanism underlying the bacterial infection-induced activation of DNA damage response in host mammalian cells.
authors.affiliation: Department of Life Science, Sogang University, Seoul, Korea.
authors.forename: Kwanghyun
authors.initials: K
authors.lastname: Lee
authors.affiliation: Department of Life Science, Sogang University, Seoul, Korea.
authors.forename: Jae Eun
authors.initials: JE
authors.lastname: Jeong
authors.affiliation: Department of Life Science, Sogang University, Seoul, Korea.
authors.forename: In Hwang
authors.initials: IH
authors.lastname: Kim
authors.affiliation: Department of Life Science, Sogang University, Seoul, Korea.
authors.forename: Kun-Soo
authors.initials: KS
authors.lastname: Kim
authors.affiliation: Department of Life Science, Sogang University, Seoul, Korea.
authors.forename: Bong-Gun
authors.initials: BG
authors.lastname: Ju
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D064447:Checkpoint Kinase 2 / Q000235:genetics / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects*; D004151:Dipeptides / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D018613:Microscopy, Confocal; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013481:Superoxides / Q000378:metabolism
chemical_list: D004151:Dipeptides; C468783:H2AX protein, human; D006657:Histones; D010456:Peptides, Cyclic; D017382:Reactive Oxygen Species; C118540:cyclo(phenylalanyl-prolyl); D013481:Superoxides; D064447:Checkpoint Kinase 2; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: DNA damage; comet assay; cyclo dipeptide; cyclo(phenylalanine-proline); reactive oxygen species