title: Triphlorethol-a improves the non-homologous end joining and base-excision repair capacity impaired by formaldehyde.
abstract: Formaldehyde (HCHO) generates reactive oxygen species (ROS) that induce DNA base modifications and DNA strand breaks and contributes to mutagenesis and other pathological processes. DNA non-homologous end-joining (NHEJ), a major mechanism for repairing DNA double-stranded breaks (DSB) in mammalian cells, involves the formation of a Ku protein heterodimer and recruitment of a DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to the site of DNA damage. HCHO treatment induced DSB and decreased the protein expressions of Ku 70 and phosphorylated DNA-PKcs. Triphlorethol-A reduced DNA strand breaks and restored the expression of NHEJ-related proteins. In response to oxidative DNA base damage, 8-oxoguanine DNA glycosylase 1 (OGG1) plays a vital role in repair of 8-hydroxy-2'-deoxyguanosine (8-OhdG) via the base-excision repair (BER) process. In this study, HCHO significantly increased 8-OhdG levels, whereas triphlorethol-A lowered 8-OhdG levels. Suppression of 8-OhdG formation by triphlorethol-A was related to enhanced OGG1 protein expression. Triphlorethol-A also enhanced the expression of phosphorylated Akt (the active form of Akt), a regulator of OGG1, which was found to be decreased by HCHO treatment. The phosphoinositol 3-kinase (PI3K)-specific inhibitor LY294002 abolished the cytoprotective effects induced by triphlorethol-A, suggesting that OGG1 restoration by triphlorethol-A is involved in the PI3K/Akt pathway. These results suggest that triphlorethol-A may protect cells against HCHO-induced DNA damage via enhancement of NHEJ and BER capacity.
authors.affiliation: School of Medicine and Veterinary Medical Research Institute, Jeju National University, Jeju, Korea.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.forename: Kyoung Ah
authors.initials: KA
authors.lastname: Kang
authors.forename: Mei Jing
authors.initials: MJ
authors.lastname: Piao
authors.forename: Ki Cheon
authors.initials: KC
authors.lastname: Kim
authors.forename: Nam Ho
authors.initials: NH
authors.lastname: Lee
authors.forename: Ho Jin
authors.initials: HJ
authors.lastname: You
authors.forename: Jin Won
authors.initials: JW
authors.lastname: Hyun
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects*; D051747:DNA-Activated Protein Kinase / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D005557:Formaldehyde / Q000633:toxicity*; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010696:Phloroglucinol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; C504400:triphlorethol-A; D005557:Formaldehyde; D000080242:8-Hydroxy-2'-Deoxyguanosine; D010696:Phloroglucinol; D051747:DNA-Activated Protein Kinase; D003849:Deoxyguanosine