Structure and activity of the Cdc45-Mcm2-7-GINS (CMG) complex, the replication helicase

Abstract

Highly efficient unwinding of double-stranded DNA is an essential prerequisite for duplication of the genetic material. In eukaryotes this process is catalysed by the CMG (Cdc45-Mcm2-7-GINS) complex, which is composed by 11 proteins: the Cdc45 replication factor, the hetero-hexameric Mcm2-7 and the tetrameric GINS complex. Although the Mcm2-7 is the helicase motor, in the absence of the other components the purified Mcm complex displays only a weak and labile helicase activity; in contrast, a stable complex comprising Cdc45, Mcm2-7 and GINS can be co-expressed and/or reconstituted, and shows a robust helicase activity. Despite its importance, many questions regarding the function of the CMG are still open. Although we do not yet have all the answers, over the last few years a number of studies have been published, including detailed biochemical characterisation of the CMG, the atomic structures of active archaeal proteins and the electron microscopy models of larger macromolecular complexes. All of this information is contributing to build a coherent picture of the structure and function of this complex machinery. In this chapter the current knowledge on the structure and function of the single components of the CMG and the whole complex is summarised, and the putative conformational changes that are necessary to trigger the helicase activity are discussed. As all the components of the CMG complex are hallmarks of cell proliferation and therefore are putative tumour biomarkers and potential drug targets, a full understanding of the structure and activity of this complex is therefore a prerequisite for the full exploitation of its potential in cancer diagnostics and therapy.