GEMC1 is a novel TopBP1-interacting protein involved in chromosomal DNA replication

Abstract

Chromosomal DNA must be precisely replicated in each cell cycle in order to ensure maintenance of genome stability. Most of the factors controlling this process have been identified in lower eukaryotes. Several factors involved in DNA replication are also important for the cellular response to stress conditions. However, the regulation of DNA replication in multi-cellular organisms is still poorly understood. Using the Xenopus laevis egg cell-free system, we have recently identified a novel vertebrate protein named GEMC1 required for DNA replication. xGEMC1 is a Cyclin dependent kinase (CDK) target required forCdc45 loading onto chromatin and it interacts with the checkpoint and replication factor TopBP1, which promotes its binding to chromatin during prereplication complex formation. Here we discuss our recent findings and propose possible roles for GEMC1. Interestingly, recent studies have identified other proteins with analogous functions, showing a higher level of complexity in metazoan replication control compared to lower eukaryotes.

Figure 1

Replication origins are licensed after the loading of MCM2–7 helicase complexes. This process is conserved in all eukaryotes and requires the action of Cdt1 and Cdc6, which are recruited in G₁-phase together with Orc1–6 (pre-RC). In S-phase, active CDKs and DDKs allow MCMs activation thanks to the recruitment of Cdc45 and other additional factors to the pre-RC. In yeast, Sld2 and Sld3 are the main CDK targets required for this step; they both interact with Dpb11 leading to Cdc45 recruitment and origin firing. In higher eukaryotes different Sld2/3 like-proteins (pentagons) are involved in this step. In particular, Gemc1 is phosphorylated by CDK and interacts with TopBP1 for the recruitment of Cdc45.

Figure 2

Possible roles of GEMC1 in DNA damage condition (see text).