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

Federico, Mario and Symonds, Catherine E. and Bagella, Luigi Marco and Rizzolio, Flavio and Fanale, Daniele and Russo, Antonio and Giordano, Antonio (2010) R-Roscovitine (Seliciclib) prevents DNA damage-induced cyclin A1 upregulation and hinders non-homologous end-joining (NHEJ) DNA repair. Molecular Cancer, Vol. 9 , p. 1-14. ISSN 1476-4598. Article.

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DOI: 10.1186/1476-4598-9-208

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.

Item Type:Article
ID Code:5374
Status:Published
Refereed:Yes
Uncontrolled Keywords:R-Roscovitine, Non-Homologous End-Joining (NHEJ), DNA
Subjects:Area 05 - Scienze biologiche > BIO/10 Biochimica
Divisions:001 Università di Sassari > 01 Dipartimenti > Scienze biomediche
Publisher:BioMed Central
ISSN:1476-4598
Copyright Holders:© 2010 Federico et al.; licensee BioMed Central Ltd.
Deposited On:28 Jan 2011 08:41

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