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R-Roscovitine (Seliciclib) prevents DNA damage-induced cyclin A1 upregulation and hinders non-homologous end-joining (NHEJ) DNA repair

Mario Federico125*, Catherine E Symonds1, Luigi Bagella13, Flavio Rizzolio14, Daniele Fanale2, Antonio Russo12 and Antonio Giordano146*

Author Affiliations

1 Sbarro Health Research Organization, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania, USA

2 Department of Surgery and Oncology, University of Palermo, Palermo, Italy

3 Division of Biochemistry and Biophysics, Department of Biomedical Sciences, National Institute of Biostructures and Biosystems, University of Sassari, Sassari, Italy

4 Program in Genetic Oncology, Department of Human Pathology and Oncology, University of Siena, Siena, Italy

5 Dipartmento Discipline Chirurgiche ed Oncologiche, sezione di Oncologia Medica, Policlinico Universitario Paolo Giaccone, via del Vespro 127, 90127, Palermo Italy

6 SHRO, Bio-life Sciences Building Suite 400, 1900 North 12th St., Philadelphia, PA 19122, USA

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Molecular Cancer 2010, 9:208  doi:10.1186/1476-4598-9-208

Published: 4 August 2010

Abstract

Background

CDK-inhibitors can diminish transcriptional levels of cell cycle-related cyclins through the inhibition of E2F family members and CDK7 and 9. Cyclin A1, an E2F-independent cyclin, is strongly upregulated under genotoxic conditions and functionally was shown to increase NHEJ activity. Cyclin A1 outcompetes with cyclin A2 for CDK2 binding, possibly redirecting its activity towards DNA repair. To see if we could therapeutically block this switch, we analyzed the effects of the CDK-inhibitor R-Roscovitine on the expression levels of cyclin A1 under genotoxic stress and observed subsequent DNA damage and repair mechanisms.

Results

We found that R-Roscovitine alone was unable to alter cyclin A1 transcriptional levels, however it was able to reduce protein expression through a proteosome-dependent mechanism. When combined with DNA damaging agents, R-Roscovitine was able to prevent the DNA damage-induced upregulation of cyclin A1 on a transcriptional and post-transcriptional level. This, moreover resulted in a significant decrease in non-homologous end-joining (NHEJ) paired with an increase in DNA DSBs and overall DNA damage over time. Furthermore, microarray analysis demonstrated that R-Roscovitine affected DNA repair mechanisms in a more global fashion.

Conclusions

Our data reveal a new mechanism of action for R-Roscovitine on DNA repair through the inhibition of the molecular switch between cyclin A family members under genotoxic conditions resulting in reduced NHEJ capability.