The Spi1/PU.1 transcription factor accelerates replication fork progression by increasing PP1 phosphatase in leukemia - Archive ouverte HAL Access content directly
Journal Articles Oncotarget Year : 2017

The Spi1/PU.1 transcription factor accelerates replication fork progression by increasing PP1 phosphatase in leukemia

Abstract

Oncogenes trigger replicative stress that can lead to genetic instability, which participates in cancer progression. Thus, determining how cells cope with replicative stress can help our understanding of oncogenesis and lead to the identification of new antitumor treatment targets. We previously showed that constitutive overexpression of the oncogenic transcription factor Spi1/PU.1 leads to pre-leukemic cells that have a shortened S phase duration with an increased replication fork speed and increased mutability in the absence of DNA breaks. Here, we demonstrate that the S phase checkpoint protein CHK1 is maintained in a low phosphorylation state in Spi1/PU.1-overexpressing cells and provide evidence that this is not due to negative control of its primary kinase ATR. Notably, we found that the expression of the CHK1 phosphatase PP1α is increased in Spi1/PU.1-overexpressing cells. By exogenously modulating its activity, we demonstrate that PP1α is required to maintain CHK1 in a dephosphorylated state and, more importantly, that it is responsible for the accelerated replication fork progression in Spi1/PU.1-overexpressing cells. These results identify a novel pathway by which an oncogene influences replication in the absence of DNA damage
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Origin : Publication funded by an institution

Dates and versions

hal-02424493 , version 1 (08-04-2024)

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Pauline Rimmelé, Michela Esposito, Laure Delestré, Jean-Hugues Guervilly, Maya Ridinger-Saison, et al.. The Spi1/PU.1 transcription factor accelerates replication fork progression by increasing PP1 phosphatase in leukemia. Oncotarget, 2017, 8 (23), ⟨10.18632/oncotarget.16183⟩. ⟨hal-02424493⟩
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