Regulation of polo-like kinase 1 by DNA damage and PP2A/B55α

Abstract

These authors equally contributed to this work.Keywords: B55a, checkpoint recovery, DNA damage, Plk1, PP2AIn addition to governing mitotic progression, Plk1 also suppresses the activation of the G2 DNA damage checkpoint and promotes checkpoint recovery. Previous studies have shown that checkpoint activation after DNA damage requires inhibition of Plk1, but the underlying mechanism of Plk1 regulation was unknown. In this study we show that the specific phosphatase activity toward Plk1 Thr-210 in interphase Xenopus egg extracts is predominantly PP2A-dependent, and this phosphatase activity is upregulated by DNA damage. Consistently, PP2A associates with Plk1 and the association increases after DNA damage. We further revealed that B55a, a targeting subunit of PP2A and putative tumor suppressor, mediates PP2A/Plk1 association and Plk1 dephosphorylation. B55a and PP2A association is greatly strengthened after DNA damage in an ATM/ATR and checkpoint kinase-dependent manner. Collectively, we report a phosphatase-dependent mechanism that responds to DNA damage and regulates Plk1 and checkpoint recovery.

Nutritional cell cycle reprogramming reveals that inhibition of Cdk1 is required for proper MBF-dependent transcription

“…These cells enter into mitosis and undergo mitotic catastrophe, indicating that PP2A activity is also important in preventing entry into mitosis in response to the activation of the DNA damage checkpoint, suggesting that both inhibition of Cdk1/ cyclin B and activation of PP2A are required to delay the cell cycle in G2 upon DNA damage. In agreement with this idea, upregulation of PP2A phosphatase activity in the presence of DNA damage has been described in Xenopus egg extracts (Wang et al, 2015).…”

ATM /Wip1 activities at chromatin control Plk1 re‐activation to determine G2 checkpoint duration

“…Key targets of Chk1/Chk2/MK2 are Cdc25 phosphatases and their degradation or functional inactivation results in a rapid decrease in Cdk1 activity and suppression of cell cycle progression (Peng et al, 1997;Mailand et al, 2000;Reinhardt et al, 2007). In parallel, Plk1 is inactivated by ATM-mediated dephosphorylation of Thr210 by phosphatase PP2A/B55a and by ATR-mediated degradation of Bora, the co-factor necessary for activation of Plk1 (Qin et al, 2013;Wang et al, 2015;Bruinsma et al, 2017). In addition to this rapid response, a checkpoint is reinforced by activation of p53 and expression of the Cdk inhibitor p21 cip/waf and also by premature activation of APC/C-Cdh1 that results in degradation of multiple proteins including Plk1 (Bunz et al, 1998;de Boer et al, 2016).…”

LB100, a small molecule inhibitor of PP2A with potent chemo- and radio-sensitizing potential

“…29 PP2A also acts on other mitotic mediators, including the key mitosis-specific kinase, Polo-like kinase 1 (PLK1), which localizes to centrosomes during mitosis and when inactivated by PP2A is an important hallmark of G2/M arrest and activation of the DNA damage response. 30 PP2A also participates in a negative feedback loop, antagonizing Aurora B and Plk1 kinases, thus maintaining the spindle assembly checkpoint until microtubules are properly attached to chromosome kinetichores. 31,32 PP2A As a Tumor Suppressor PP2A has been classically characterized as a tumor suppressor gene.…”