Protein phosphatase 2A has an essential role in the activation of γ-irradiation-induced G2/M checkpoint response

Abstract

G2/M checkpoint activation after DNA damage results in G2/M cell cycle arrest that allows time for DNA repair before the entry of cells into mitosis. Activation of G2/M checkpoint involves a series of signaling events, which include activation of ataxia telangiectecia-mutated and Rad3-related (ATR) and Chk1 kinases and inhibition of Cdc2/Cyclin B activity. Studies presented in this report show that serine (Ser)/threonine (Thr) protein phosphatase 2A (PP2A) has an important role in G2/M checkpoint activation in response to γ-irradiation (IR) exposure. Using PP2A inhibitors, as well as siRNA targeting various forms of Ser/Thr protein phosphatases, results presented in this report show that specific PP2A inhibition abrogates IR-induced activation of ATR and Chk1 kinases, as well as phosphorylation of Cdc2-Tyr15, and attenuates IR-induced G2/M arrest. These results suggest an important regulation of PP2A on IR-induced G2/M checkpoint signaling response.

Loss of PPP2R2A Inhibits Homologous Recombination DNA Repair and Predicts Tumor Sensitivity to PARP Inhibition

“…However, consistent with the idea that protein phosphatases are not just negative regulators of DNA repair signaling, selective inhibition of PP2A activity impairs DNA repair (7)(8)(9). PP2A function is also essential for activation of cell-cycle checkpoints in response to irradiation (10,11). One potential explanation for this apparent discrepancy is that several distinct PP2A complexes may modulate different steps of the DNA repair process.…”

Recognition, signaling, and repair of DNA double-strand breaks produced by ionizing radiation in mammalian cells: The molecular choreography

“…1.2). A PPA2 siRNA knockdown study using MCF7 tumor cells shows that ATM still displays IR-induced activation in the absence of PPA2 [138]. A negative regulator of PPA2 phosphatase is also identified [139] and may participate in this regulation of ATM phosphorylation.…”

Lovastatin protects keratinocytes from DNA damage-related pro-apoptotic stress responses stimulated by anticancer therapeutics

“…JNK and p38 kinase have been shown to influence replication stress-associated checkpoint control mechanisms [66]. Recently it has been reported that protein phosphatase 2A (PP2A) is able to antagonize ATR-regulated Chk1 phosphorylation [67,68]. Bearing in mind these reports, the inhibitory effect of lovastatin on IR and Doxo-stimulated increase in pChk1 levels might result either from (i) reduced activation or inhibition of Chk1 phosphorylating kinases or (ii) increase in the activity of Chk1 desphosphorylating enzymes such as PP2A.…”