Closing the MCM cycle at replication termination sites

Abstract

The initiation of eukaryotic DNA replication is a highly regulated process conserved from yeast to human. The past decade has seen significant advances in understanding how the CMG (Cdc45‐MCM‐GINS) replicative helicase is loaded onto DNA. However, very little was known on how this complex is removed from chromatin at the end of S phase. Two papers in a recent issue of Science [1], [2] show that in yeast and in Xenopus, the CMG complex is unloaded at replication termination sites by an active mechanism involving the polyubiquitylation of Mcm7.

Figure 1

The MCM cycle. In eukaryotes, the Mcm2-7 complex is loaded on chromatin upon exit from mitosis, exclusively during G₁, by the ORC complex, Cdc6 and Cdt1 to form the pre-replicative complex (pre-RC). At the G₁/S transition, cyclin- and Dbf4-dependent kinases (CDK and DDK) promote the recruitment of Cdc45 and the GINS complex, which form the CMG replicative helicase together with Mcm2-7. The CMG complex acts in front of the replisome to separate parental DNA strands. Upon termination of DNA replication, Mcm7 is ubiquitylated to promote the disassembly of the CMG helicase by Cdc48/p97. This mechanism is conserved in S. cerevisiae and in Xenopus. In yeast, the ubiquitylation of Mcm7 depends on Dia2, an integral component of the replisome. The ubiquitin ligase responsible for Mcm7 ubiquitylation in metazoans is currently unknown.