Control of the Cdc6 replication licensing factor in metazoa: the role of nuclear export and the CUL4 ubiquitin ligase

Abstract

A central requirement to maintain genome stability is that DNA replication must be tightly controlled so that genomic DNA is replicated only once in a single cell cycle. The prevention of DNA re-replication is achieved by restricting the assembly of pre-replicative complexes (pre-RCs) to the period prior to S phase, and ensuring that pre-RCs cannot reform during S phase. The regulation of the replication licensing factors Cdt1 and Cdc6 during S phase is critical to prevent the reformation of pre-RCs. In yeast, Cdc6 is degraded during S phase to block DNA re-replication. In mammals, Cdc6 is exported from the nucleus; however, a variable percentage of endogenous Cdc6 remains nuclear throughout S phase. The perdurance of nuclear Cdc6 has led a number of groups to question whether the nuclear export of Cdc6 is relevant in restricting its activity. A recent study in C. elegans shows that the nuclear export of Cdc6 is in fact critical to prevent DNA re-replication. This work also identifies the CUL-4 ubiquitin ligase as a master regulator that controls DNA replication by regulating both Cdt1 and Cdc6 replication licensing factors.