MicroRNA-29a regulates the benzo[a]pyrene dihydrodiol epoxide-induced DNA damage response through Cdc7 kinase in lung...

Cdc7 kinase is a key regulator of DNA replication and has an important role in the cellular DNA damage response by controlling checkpoint signaling and cell survival. Yet, how the activity of Cdc7 kinase is regulated is poorly understood. In silico analysis identified microRNA-29 (miR-29)-binding sites in the 3'-untranslated region (UTR) of both Cdc7 and its activating subunit Dbf4. We show that miR-29a binds to Cdc7 and Dbf4 3'-UTRs and regulates kinase levels. We find that in response to DNA damage, upregulation of Cdc7 kinase correlates with a downregulation in miR-29a. Enforced miR-29a expression prevents the accumulation of Cdc7 in response to the environmental genotoxin, benzo[a]pyrene dihydrodiol epoxide (BPDE) present in cigarette smoke, resulting in aberrant checkpoint signaling and increased cell lethality. As BPDE sensitivity was rescued by overexpression of miRNA-resistant Cdc7/Dbf4, we propose that Cdc7 kinase is an important target of miR-29a in determining cell survival from genotoxic stress caused by this environmental toxin.