The Cdk2-c-Myc-miR-571 Axis Regulates DNA Replication and Genomic Stability by Targeting Geminin.

Abstract

DNA rereplication leads to genomic instability and has been implicated in the pathology of a variety of human cancers. Eukaryotic DNA replication is tightly controlled to ensure it occurs only once during each cell cycle. Geminin is a critical component of this control, it prevents DNA rereplication from occurring during S, G₂, and early M phases by preventing MCM helicases from forming prereplication complexes. Geminin is targeted for degradation by the anaphase-promoting complex (APC/C) from anaphase through G₁-phase, however, accumulating evidence indicates that Geminin is downregulated in late S-phase due to an unknown mechanism. Here, we used a high-throughput screen to identify miRNAs that can induce excess DNA replication and found that miR-571 could reduce the protein level of Geminin in late S-phase independent of the APC/C. Furthermore, miR-571 regulated efficient DNA replication and S-phase cell-cycle progression. Strikingly, c-Myc suppressed miR-571 expression by binding directly to the miR-571 promoter. At the beginning of S-phase, Cdk2 phosphorylated c-Myc at Serine 62, promoting its association with the miR-571 promoter region. Collectively, we identify miR-571 as the first miRNA that prevents aberrant DNA replication and the Cdk2-c-Myc-miR-571 axis as a new pathway for regulating DNA replication, cell cycle, and genomic stability in cancer cells. SIGNIFICANCE: These findings identify a novel regulatory mechanism that is critical for maintaining genome integrity by regulating DNA replication and cell-cycle progression.