Abstract
Proper control of DNA replication is critical to ensure genomic integrity during cell proliferation. In addition, differential regulation of the DNA replication program during development can change gene copy number to influence cell size and gene expression. Drosophila melanogaster serves as a powerful organism to study the developmental control of DNA replication in various cell cycle contexts in a variety of differentiated cell and tissue types. Additionally, Drosophila has provided several developmentally regulated replication models to dissect the molecular mechanisms that underlie replication-based copy number changes in the genome, which include differential underreplication and gene amplification. Here, we review key findings and our current understanding of the developmental control of DNA replication in the contexts of the archetypal replication program as well as of underreplication and differential gene amplification. We focus on the use of these latter two replication systems to delineate many of the molecular mechanisms that underlie the developmental control of replication initiation and fork elongation.
Highlights
Proper control of DNA replication is critical to ensure genomic integrity during cell proliferation
Through the molecular study of DNA replication initiation and elongation, it is clear that the mechanisms that regulate origin activity and replication fork progression are diverse and complex, in the context of development
Under the regulation of two kinases, S phase Cyclin-Dependent Kinase (CDK) and Dbf4-Dependent Kinase (DDK), the MCM2–7 complex is joined by CDC45 and the Go-Ichi-Ni-San (GINS) complex, a four-membered complex composed of Sld5, Psf1, Psf2, and Psf3
Summary
The genome must be completely and accurately replicated to maintain the integrity of genetic information across cell generations. Through the molecular study of DNA replication initiation and elongation, it is clear that the mechanisms that regulate origin activity and replication fork progression are diverse and complex, in the context of development. The replication initiation factor cell division cycle 6 (Cdc6) is recruited to the origin to form a complex with ORC. ORC and Cdc work cooperatively to recruit the initiation factor Cdt1 [Double Parked (DUP) in Drosophila] and the six-membered Minichromosome Maintenance (MCM) replicative helicase complex. The CDC45/MCM2–7/GINS (CMG) complex forms the functional replicative helicase (Bleichert et al 2017; Parker et al 2017). As two MCM2–7 hexamers are loaded onto a single origin of replication, two CMG complexes establish the independent, bidirectional replication forks after origin activation (Figure 1)
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