Cyclin A1 may have a role in carcinogenesis, as it has been found to be over expressed neverless in acute Inhibitors,Modulators,Libraries myeloid leukemia and var ious other tumour types, however, its role in can cer is still particularly obscure. In somatic non testicular tissues, cyclin A1 is not expressed or is expressed at very low basal levels. After genotoxic insult, cyclin A1 mRNA is upregulated Inhibitors,Modulators,Libraries in vitro and in vivo. At a molecular level, human CDK2/cyclin A1 complexes interact with members of the Ku family and phosphory late Ku70, a pivotal player in the non homolo gous end joining double strand break repair pathway. Furthermore, under genotoxic condi tions the kinase activity of CDK2/cyclin A1 complex increases, while the relative kinase activity of CDK2/ cyclin A2 decreases and the CDK2/cyclin A1 complex out competes with CDK2/cyclin A2 for Ku70 binding.

Moreover, it has recently been found that CDK2 phosphorylation Inhibitors,Modulators,Libraries status and structure changes upon the cyclin A family member with which it is bound suggesting a non redundant function between CDK2/ cyclin A1 and CDK2/cyclin A2 complexes. Finally cyclin A1 knockout mice and Xenopus embryos exhibited a clear defect in DNA repair and are more prone to undergo apoptosis. Taken together these data support that during geno toxic stress differential transcriptional levels and activity of cyclin A family members may redirect CDK2 toward DNA repair resulting in a modulation of NHEJ. Since one of the most relevant effects of CDK inhibitors is the downregulation of cell cycle related cyclins, we investi gated if the inhibition of DNA repair mechanisms by Roscovitine may also occur through the modulation of the expression levels of cyclin A family members.

Phy siological CDK inhibition, Inhibitors,Modulators,Libraries in fact, results in cyclin downregulation through the inhibition of E2F family transcription factors, which drive and regulate cell cycle related cyclin transcription. Given that the promoter of the Inhibitors,Modulators,Libraries cyclin A1 gene, CCNA1, is different from the other cell cycle related cyclins, not being under the regulation of E2Fs, here we analyzed the effects of Roscovitine on cyclin A1 expression and modulation of DNA repair mechanisms. We demonstrated that www.selleckchem.com/products/Enzastaurin.html under DNA dama ging conditions cyclin A1 is strongly upregulated and localizes to the nucleus. Although Roscovitine alone was not sufficient to reduce the basal levels of cyclin A1, in contrast to cell cycle related cyclins, Roscovitine treat ment could abolish the DNA damage induced cyclin A1 upregulation, reducing NHEJ and significantly hindering DNA repair over time. Results DNA damage induces a switch in the respective levels of A family cyclins We first compared mRNA levels of both members of the cyclin A family after treatment with increasing doses of Doxorubicin, a well known inducer of DNA DSBs.