Abstract
DNA replication results in the doubling of the genome prior to cell division. This process requires the assembly of 50 or more protein factors into a replication fork. Here, we review recent structural and biochemical insights that start to explain how specific proteins recognize DNA replication origins, load the replicative helicase on DNA, unwind DNA, synthesize new DNA strands, and reassemble chromatin. We focus on the minichromosome maintenance (MCM2-7) proteins, which form the core of the eukaryotic replication fork, as this complex undergoes major structural rearrangements in order to engage with DNA, regulate its DNA-unwinding activity, and maintain genome stability.
Highlights
The genomic sites where DNA replication is initiated are known as DNA replication origins (Marahrens and Stillman 1992; Hyrien 2016)
minichromosome maintenance 2–7 (MCM2–7) is the core of the replicative DNA helicase and consists of six subunits that have a spiral arrangement with a gap at the Mcm2/5 interface (Costa et al 2011; Ticau et al 2017; Zhai et al 2017)
Cdt1 release is associated with a structural change, as it promotes the closure of the MCM2–7 ring (Ticau et al 2017)
Summary
The genomic sites where DNA replication is initiated are known as DNA replication origins (Marahrens and Stillman 1992; Hyrien 2016). Activation of the MCM2–7 DH, termed preinitiation complex (pre-IC) formation, is a highly complex process and has been intensively studied in budding yeast It depends on Dbf4-depedent kinase (DDK) Cdc and Sphase-specific cyclin-dependent kinase (CDK) and a large number of activation factors, including Sld, Cdc, Sld, Dpb, GINS (from the Japanese go-ichi-ni-san, meaning 5-1-2-3, after the four related subunits of the complex: Sld, Psf, Psf and Psf3), polymerase ε, and Mcm (Fig. 1F; Heller et al 2011; Yeeles et al 2015). One or more MCM2–7 DHs are loaded, but only a minority becomes transformed into active CMGs during S phase; with the remaining MCM2–7 DHs serving as “dormant origins,” which become activated only if a proximal replication fork becomes terminally arrested (Woodward et al 2006; Ibarra et al 2008)
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