The Spi1/PU.1 transcription factor accelerates replication fork progression by increasing PP1 phosphatase in leukemia
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Pauline Rimmelé1,2, Michela Esposito3,4, Laure Delestré3,4, Jean-Hugues Guervilly3,5, Maya Ridinger-Saison1,2, Emmanuelle Despras3,5, Françoise Moreau-Gachelin1,2, Filippo Rosselli3,5, Christel Guillouf1,2,3,4,6
1Institut Curie, Paris, France
2Inserm U830, Paris, France
3Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France
4Inserm U1170, Villejuif, France
5CNRS UMR8200, Equipe Labellisée La Ligue Contre Le Cancer, Villejuif, France
6CNRS, Paris, France
Christel Guillouf, email: [email protected]
Keywords: DNA replication, leukemia, Spi1/PU.1 oncogene, CHK1, PP1
Received: January 31, 2017 Accepted: March 03, 2017 Published: March 14, 2017
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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