title: PP2A-B56ϵ complex is involved in dephosphorylation of γ-H2AX in the repair process of CPT-induced DNA double-strand breaks.
abstract: Phosphorylation of histone H2AX (γ-H2AX) in response to DNA double-strand breaks (DSBs) should be eliminated from the sites of DNA damage to fulfill the DNA repair and release cells from the growth arrest. Previous study showed that protein phosphatase 2A (PP2A) interact with γ-H2AX that lead to the dephosphorylation of γ-H2AX. Here, we examined the effects of suppression of PP2A regulatory subunits on dephosphorylation of γ-H2AX in human embryonic kidney epithelial cells (HEK) treated by topoisomerase I inhibitor camptothecin (CPT). We found that cells with suppression of B55α or B56ϵ were more sensitive to DNA damage agents. Suppression of B56ϵ led to persistence of γ-H2AX, resulting in prolonged DSBs repair and increased chromatin instability measured by comet assay. In addition, the deficiency of B56ϵ impaired the cell cycle regulation and the DNA repair pathway of homologous recombination (HR). Notably, we detected that PP2A B56ϵ subunit was involved directly in dephosphorylation of γ-H2AX and translocated from cytoplasm to nucleus upon the treatment of CPT. Our findings demonstrate that PP2A holoenzyme containing B56ϵ is responsible for the dephosphorylation of γ-H2AX and regulation of DNA repair of DSBs induced by CPT.
authors.affiliation: Institute for Chemical Carcinogenesis, Guangzhou Medical University, Guangzhou 510182, China; College of Pharmacy, Jinan University, Guangzhou 510632, China.
authors.forename: Xiuying
authors.initials: X
authors.lastname: Li
authors.affiliation: Institute for Chemical Carcinogenesis, Guangzhou Medical University, Guangzhou 510182, China.
authors.forename: Anuo
authors.initials: A
authors.lastname: Nan
authors.affiliation: College of Pharmacy, Jinan University, Guangzhou 510632, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Institute for Chemical Carcinogenesis, Guangzhou Medical University, Guangzhou 510182, China.
authors.forename: Yongzhong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Institute for Chemical Carcinogenesis, Guangzhou Medical University, Guangzhou 510182, China. Electronic address: yandong_lai@163.com.
authors.forename: Yandong
authors.initials: Y
authors.lastname: Lai
mesh_terms: D021581:Active Transport, Cell Nucleus; D002166:Camptothecin / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D042822:Genomic Instability / Q000187:drug effects; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology*; D014162:Transfection
chemical_list: C468783:H2AX protein, human; D006657:Histones; C525690:PPP2R5A protein, human; C525692:PPP2R5E protein, human; D059004:Topoisomerase I Inhibitors; C572369:PP2A-B56alpha protein, human; D054648:Protein Phosphatase 2; D002166:Camptothecin
keywords: B56ϵ; Camptothecin; Double-strand break repair; Histone H2AX; Protein phosphatase 2A