PP2A-B56ϵ complex is involved in dephosphorylation of γ-H2AX in the repair process of CPT-induced DNA double-strand breaks

Toxicology
Xiuying LiYandong Lai

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.

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Citations

Dec 23, 2015·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Andrej BesseOndrej Slaby
Nov 10, 2017·FEBS Letters·Goce Taleski, Estelle Sontag
Jan 16, 2020·International Journal of Molecular Sciences·Adrián Campos, Andrés Clemente-Blanco
Oct 9, 2020·Nature Communications·Michał S BarskiGoedele N Maertens
Apr 11, 2021·Proceedings of the National Academy of Sciences of the United States of America·Valeska HelfingerKatrin Schröder
Sep 29, 2019·Mutation Research. Genetic Toxicology and Environmental Mutagenesis·Alena GabelovaMonika Sramkova

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