Regulation of the Aurora-A gene following topoisomerase I inhibition: implication of the Myc transcription Factor

Sandy Courapied,Marie-Bérangère Troadec,Sandrine Giraud,Isabelle Valo,Benjamin Barré,Erick Gamelin,Olivier Coqueret,Claude Prigent,Julia Cherier,Arnaud Vigneron

doi:10.1186/1476-4598-9-205

Sandy Courapied, Marie-Bérangère Troadec + Show 8 more

Open Access

https://doi.org/10.1186/1476-4598-9-205

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Abstract

During the G2 phase of the cell cycle, the Aurora-A kinase plays an important role in centrosome maturation and progression to mitosis. In this study, we show in colorectal cell lines that Aurora-A expression is downregulated in response to topoisomerase I inhibition. Using chromatin immunoprecipitation assays, we have observed that the Myc transcription factor and its Max binding partner are associated with the Aurora-A promoter during the G2 phase of the cell cycle. RNA interference experiments indicated that Myc is involved in the regulation of the Aurora-A gene. Following topoisomerase I inhibition, the expression of Myc decreased whereas Mad was upregulated, and the association of Myc and Max with the promoter of the kinase was inhibited. In parallel, an increased association of Mad and Miz-1 was detected on DNA, associated with an inhibition of the recruitment of transcriptional coactivators. Interestingly, a gain of H3K9 trimethylation and HP1γ recruitment was observed on the Aurora-A promoter following sn38 treatment, suggesting that this promoter is located within SAHF foci following genotoxic treatment. Since Aurora-A is involved in centrosome maturation, we observed as expected that topoisomerase I inhibition prevented centrosome separation but did not affect their duplication. As a consequence, this led to G2 arrest and senescence induction.These results suggest a model by which the Aurora-A gene is inactivated by the G2 checkpoint following topoisomerase I inhibition. We therefore propose the hypothesis that the coordinated overexpression of Myc and Aurora-A, together with a downregulation of Mad and Miz-1 should be tested as a prognosis signature of poor responses to topoisomerase I inhibitors.

Highlights

The response to genotoxic treatments relies to a large extent on the activation of the ATM and ATR kinases and on the consequent upregulation of chk1 and chk2 signaling [1,2,3]
Following topoisomerase I inhibition, Myc/Max binding is inhibited, Mad and Miz-1 associate with this promoter and this is associated with transcriptional downregulation. These results indicate that Aurora-A is downregulated in response to topoisomerase I inhibition. We propose that this inhibition plays an important role during the G2 checkpoint in parallel to p53 induction and cdc25C inactivation
Topoisomerase I inhibition induced a downregulation of Aurora-A expression We first wanted to confirm in colorectal cell lines that Aurora-A was mainly expressed during the G2 phase of the cell cycle

Summary

Introduction

The response to genotoxic treatments relies to a large extent on the activation of the ATM and ATR kinases and on the consequent upregulation of chk and chk signaling [1,2,3] Among numerous substrates, this signaling network leads to the activation and stabilization of the p53 pathway which induces apoptosis or cell cycle arrest [4]. In association with the cyclin B-cdk complexes and cdc25C, the Aurora-A serine/threonine kinase is essential for progression to mitosis [9,10] This protein localizes in early G2 to duplicated centrosomes where it plays an important role in their maturation, separation and in the consequent assembly of the spindle apparatus. An abnormal expression of this kinase is believed to play an important role in cell transformation and genetic instability

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