Abstract
Checkpoint kinases sense replicative stress to prevent DNA damage. Here we show that the histone deacetylases HDAC1/HDAC2 sustain the phosphorylation of the checkpoint kinases ATM, CHK1 and CHK2, activity of the cell cycle gatekeeper kinases WEE1 and CDK1, and induction of the tumour suppressor p53 in response to stalled DNA replication. Consequently, HDAC inhibition upon replicative stress promotes mitotic catastrophe. Mechanistically, HDAC1 and HDAC2 suppress the expression of PPP2R3A/PR130, a regulatory subunit of the trimeric serine/threonine phosphatase 2 (PP2A). Genetic elimination of PR130 reveals that PR130 promotes dephosphorylation of ATM by PP2A. Moreover, the ablation of PR130 slows G1/S phase transition and increases the levels of phosphorylated CHK1, replication protein A foci and DNA damage upon replicative stress. Accordingly, stressed PR130 null cells are very susceptible to HDAC inhibition, which abrogates the S phase checkpoint, induces apoptosis and reduces the homologous recombination protein RAD51. Thus, PR130 controls cell fate decisions upon replicative stress.
Highlights
Checkpoint kinases sense replicative stress to prevent DNA damage
We found that HCT116ΔPR130 cells had significantly higher levels of pCHK1 and that MS-275 attenuated the phosphorylation of checkpoint kinase-1 (CHK1), but not of ATR, in both HCT116ΔgDNA and HCT116ΔPR130 cells (Figs. 7a,b)
Our report reveals that the epigenetic modifiers HDAC1 and HDAC2 control checkpoint kinase phosphorylation through a suppression of PR130
Summary
Checkpoint kinases sense replicative stress to prevent DNA damage. Here we show that the histone deacetylases HDAC1/HDAC2 sustain the phosphorylation of the checkpoint kinases ATM, CHK1 and CHK2, activity of the cell cycle gatekeeper kinases WEE1 and CDK1, and induction of the tumour suppressor p53 in response to stalled DNA replication. Disturbances in the progression of DNA replication forks and DNA damage activate checkpoint kinases, including ataxia telangiectasia mutated (ATM), ATM and Rad3-related (ATR), checkpoint kinase-1 (CHK1), and checkpoint kinase-2 (CHK2)[1,2,3,4,5] These kinases promote cell cycle arrest and the intra S phase checkpoint[3,4,5], which prevent fatal premature transitions of cells with incompletely replicated or damaged DNA into mitosis[6,7]. Obstructed replication forks activate ATR and its downstream targets CHK1 and ATM3,10–13 This activation of ATM and CHK1 in cells exposed to replicative stress does not require the MRE11/RAD51/Nibrin (MRN) complex that promotes autophosphorylation of ATM in response to direct DNA double-strand breaks (DSBs)[10]. Inhibitors of HDACs (HDACi) enhance the cytotoxicity of DNA-damaging chemotherapies and of drugs targeting S phase and DNA repair[42]
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