The Replication Licensing System
A special issue of Biology (ISSN 2079-7737). This special issue belongs to the section "Cell Biology".
Deadline for manuscript submissions: 31 August 2025 | Viewed by 12795
Special Issue Editor
Special Issue Information
Dear Colleagues,
The reconstitution of eukaryotic DNA replication in vitro, together with the great advances in our structural understanding of the many discrete steps required for DNA replication initiation afforded by the advent of increasingly higher resolution cryo-EM, have provided us with a far greater understanding of the eukaryotic DNA replication process than we could ever have envisaged just a decade ago.
The MCM (MiniChromosome Maintenance) proteins were first identified in budding yeast almost 40 years ago. The key to genome duplication in eukaryotes is the MCM2-7 heterohexamer: MCM2-7 forms the core of the CMG replicative helicase that unwinds DNA during the S phase to facilitate its replication.
MCM2-7 is first loaded onto chromatin as an inactive double hexamer at the sites of potential replication initiation, referred to as replication origins, during the late M and G1 phases; this MCM2-7 loading 'licenses' an origin to support one round of replication initiation in the upcoming S phase. The loading of MCM2-7 onto replication origins, a process known as 'replication licensing', requires three additional factors: ORC—the origin recognition complex, CDC6, and CDT1. Further to replication licensing, each of these factors play additional roles in the control of cell cycle progression, in processes as diverse as transcriptional regulation, the establishment of chromatid cohesion, kinetochore formation, and cytokinesis. During the S phase the MCM2-7 double hexamers are split and activated to form the CMG replicative helicase and following replication initiation CMG facilitates replication elongation as part of the replication fork. Upon replication termination, MCM2-7 proteins are removed from chromatin in a ubiquitylation-dependent manner. This dynamic association of MCM2-7 with chromatin once per cell cycle controls genome duplication and thus contributes to the maintenance of genomic stability.
The mutation or misregulation of the replication licensing proteins can generate replication stress, which results in genomic instability and has been indicated in the aetiology of human diseases: the development of cancer and the developmental disorder Meier–Gorlin Syndrome. Pharmacological intervention targeted at the replication licensing system may therefore be of considerable interest in ameliorating these disease states. Of particular interest is the distinct response of cancer and somatic cells to the inhibition of replication licensing.
In this Special Issue, to provide a complete description of the role of the replication licensing factors during the eukaryotic cell cycle, we encourage the submission of manuscripts covering all aspects of the replication licensing system, from the initiation of DNA replication, through the non-licensing roles of the replication licensing factors, to the discussion of the role of the misregulation of the replication licensing system in disease and the potential for the development of therapeutic intervention.
Dr. Peter J. Gillespie
Guest Editor
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Keywords
- cell cycle
- DNA replication
- genome stability
- replication licensing
- MCM2-7
- ORC
- Cdc6
- CDT1
- cancer
- Meier-Gorlin syndrome
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